Granulin: Difference between revisions

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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
{{Infobox protein family
| update_page = yes
| Symbol = Granulin
| require_manual_inspection = no
| Name = Granulin
| update_protein_box = yes
| image = PDB 1g26 EBI.jpg
| update_summary = yes
| width =
| update_citations = yes
| caption = the solution structure of a well-folded peptide based on the 31-residue amino-terminal subdomain of human granulin a
| Pfam = PF00396
| Pfam_clan = 
| InterPro = IPR000118
| SMART =
| PROSITE = PDOC00634
| MEROPS =
| SCOP = 1pcn
| TCDB =  
| OPM family =  
| OPM protein =  
| CAZy =  
| CDD =  
}}
}}
'''Granulin''' is a [[protein]] that in humans is encoded by the GRN [[gene]].<u href="gene"><ref name="pmid14178682">{{cite journal | vauthors = Bhandari V, Bateman A | title = Structure and chromosomal location of the human granulin gene | journal = Biochemical and Biophysical Research Communications | volume = 188 | issue = 1 | pages = 57–63 | date = October 1992 | pmid = 1417868 | doi = 10.1016/0006-291X(92)92349-3 }}</ref><ref name="pmid98266782">{{cite journal | vauthors = Zhang H, Serrero G | title = Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 24 | pages = 14202–7 | date = November 1998 | pmid = 9826678 | pmc = 24351 | doi = 10.1073/pnas.95.24.14202 | bibcode = 1998PNAS...9514202Z }}</ref><ref name="entrez2">{{cite web | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2896|title=Entrez Gene: GRN granulin|access-date=}}</ref></u> Each granulin protein is cleaved from the precursor progranulin, a 593 amino acid long and 68.5 kDa protein.<ref name="Eriksen_2008">{{cite journal | vauthors = Eriksen JL, Mackenzie IR | title = Progranulin: normal function and role in neurodegeneration | journal = Journal of Neurochemistry | volume = 104 | issue = 2 | pages = 287–97 | date = January 2008 | pmid = 17953663 | doi = 10.1111/j.1471-4159.2007.04968.x }}</ref> While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in [[developmental biology|development]], [[inflammation]], [[cell proliferation]] and [[protein homeostasis]]. The 2006 discovery of the GRN mutation in a population of patients with [[frontotemporal dementia]] has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Progranulin ==
{{GNF_Protein_box
Progranulin is the [[precursor protein]] for granulin. Cleavage of progranulin produces a variety of active 6 kDa granulin peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Cleavage of progranulin into granulin occurs either in the [[extracellular matrix]] or the [[lysosome]]. [[Elastase]], [[proteinase 3]] and [[matrix metalloproteinase]] are [[protease]]s capable of cleaving progranulin into individual granulin peptides.<ref name="Eriksen_2008" /><ref name="Paushter_2018">{{cite journal | vauthors = Paushter DH, Du H, Feng T, Hu F | title = The lysosomal function of progranulin, a guardian against neurodegeneration | journal = Acta Neuropathologica | pages = 1–17 | date = May 2018 | pmid = 29744576 | doi = 10.1007/s00401-018-1861-8 }}</ref> Progranulin and granulin can be further differentiated by their hypothesized opposing roles in the cell. While progranulin is associated with anti-[[inflammation]], cleaved granulin peptides have been implicated in pro-[[inflammation|inflammatory]] behavior. A ''[[Caenorhabditis elegans|C. elegans]]'' study showed that granulin peptides may also participate in toxic activity.<ref name="Paushter_2018" />
| image = PBB_Protein_GRN_image.jpg
 
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1g26.
== Expression ==
| PDB = {{PDB2|1g26}}
Progranulin is expressed in a wide variety of cell types both in the periphery and in the [[central nervous system]]. Progranulin expression is low in early development, but increases as cells mature.<ref name="Petkau_2014">{{cite journal | vauthors = Petkau TL, Leavitt BR | title = Progranulin in neurodegenerative disease | journal = Trends in Neurosciences | volume = 37 | issue = 7 | pages = 388–98 | date = July 2014 | pmid = 24800652 | doi = 10.1016/j.tins.2014.04.003 }}</ref> Cell types expressing progranulin include [[neuron]]s, [[microglia]], [[astrocyte]]s and [[endothelial cells]].<ref name="Kao_2017">{{cite journal | vauthors = Kao AW, McKay A, Singh PP, Brunet A, Huang EJ | title = Progranulin, lysosomal regulation and neurodegenerative disease | journal = Nature Reviews. Neuroscience | volume = 18 | issue = 6 | pages = 325–333 | date = June 2017 | pmid = 28435163 | doi = 10.1038/nrn.2017.36 }}</ref> Progranulin has been found to be highly expressed in [[microglia]] and up-regulated during injury<ref name="Kao_2017" /><ref name="Petkau_2014" /> Within the brain, progranulin mRNA is highly expressed in [[Pyramidal cell|pyramidal]], [[hippocampal]] and [[Purkinje cell]]s cells.<ref name="Eriksen_2008" />
  | Name = Granulin
 
| HGNCid = 4601
== Structure ==
| Symbol = GRN
Each individual granulin domain peptide is 60 amino acids in length. Granulin peptides are [[cysteine]] rich and capable of forming 6 disulfide bonds per residue.<ref name="Paushter_2018" /> The disulfide bonds form a central rod-like core that shuttles each individual granulin peptide into a stacked [[Beta sheet|β-sheet]] configuration.<ref name="Kao_2017" /><ref name="Eriksen_2008" /> The structure of the granulin protein is similar to the structure of proteins from protein families that consist of [[hormone]]s, [[growth factor]]s, [[ion channel modulator]]s and [[enzyme inhibitors]].<ref name="Kao_2017" /> Because of progranulin's structural similarities to these proteins, much research was done to interrogate progranulin's potential role as a growth factor. When progranulin is secreted into the [[extracellular matrix]], it is often [[glycosylated]] at 4 confirmed and 1 tentative N-linked glycosylation sites.<ref name="Kao_2017" /><ref name="Paushter_2018" /> The n-terminus of progranulin is hypothesized to be involved in the secretion of progranulin via secretory vesicles.<ref name="Kao_2017" /> Specifically, Progranulin may be involved in regulating exosome excretion.<ref>{{cite journal | vauthors = Benussi L, Ciani M, Tonoli E, Morbin M, Palamara L, Albani D, Fusco F, Forloni G, Glionna M, Baco M, Paterlini A, Fostinelli S, Santini B, Galbiati E, Gagni P, Cretich M, Binetti G, Tagliavini F, Prosperi D, Chiari M, Ghidoni R | display-authors = 6  | title = Loss of exosomes in progranulin-associated frontotemporal dementia | journal = Neurobiology of Aging | volume = 40 | pages = 41–49 | date = April 2016 | pmid = 26973102 | doi = 10.1016/j.neurobiolaging.2016.01.001 }}</ref> The C-terminus of progranulin is hypothesized to be the primary binding partner of [[Sortilin 1|SORT1]], a receptor of extracellular progranulin.<ref>{{cite journal | vauthors = Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM | display-authors = 6 | title = Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin | journal = Neuron | volume = 68 | issue = 4 | pages = 654–67 | date = November 2010 | pmid = 21092856 | pmc = 2990962 | doi = 10.1016/j.neuron.2010.09.034 }}</ref><ref name="Kao_2017" /> The structural differences between each individual granulin peptide have yet to be characterized.
| AltSymbols =; GEP; GP88; PCDGF; PEPI; PGRN
 
| OMIM = 138945
== Interactive partners ==
| ECnumber =
In the [[extracellular matrix]], progranulin binds to receptors on several cell types resulting in either activation of a [[Signal transduction|signal transduction pathway]] or engulfment into the cell. Several studies have shown progranulin's involvement in the binding of [[Sortilin 1|SORT1]] and the subsequent trafficking of bounded progranulin to the [[lysosome]].<ref name="Kao_2017" /> One recent study has shown that progranulin may actually mediate [[prosaposin]] trafficking to the lysosome via [[Sortilin 1|SORT1]].<ref>{{cite journal | vauthors = Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, Brady OA, Hernandez JC, Nishimura N, Seeley WW, Hu F | display-authors = 6 | title = Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations | language = En | journal = Nature Communications | volume = 8 | pages = 15277 | date = May 2017 | pmid = 28541286 | pmc = 5477518 | doi = 10.1038/ncomms15277 | bibcode = 2017NatCo...815277Z }}</ref> However, the absence of [[Sortilin 1|SORT1]] does not prevent exogenous progranulin from promoting neurite outgrowth or enhancing cell survival of GRN knockout cells, suggesting that other receptors are involved in mediating extracellular progranulin function<ref name="Nguyen_2013">{{cite journal | vauthors = Nguyen AD, Nguyen TA, Martens LH, Mitic LL, Farese RV | title = Progranulin: at the interface of neurodegenerative and metabolic diseases | journal = Trends in Endocrinology and Metabolism | volume = 24 | issue = 12 | pages = 597–606 | date = December 2013 | pmid = 24035620 | pmc = 3842380 | doi = 10.1016/j.tem.2013.08.003  }}</ref> For example, [[Sortilin 1|SORT1]] -/- neuronal cells are still able to bind progranulin.<ref name="Nguyen_2013" /> Other studies have suggested [[Tumor necrosis factor alpha|tumor necrosis factor]] and [[EPH receptor A2]] as potential progranulin facilitators.<ref name="Kao_2017" /> After binding to the receptor, progranulin may induce and modulate signaling pathways such as [[MAPK/ERK pathway|MAPK/ERK]], [[PI3K/AKT/mTOR pathway|PI3K/Akt]], and [[Focal adhesion kinase|FAK]].<ref name="Paushter_2018" /><ref name="Nguyen_2013" /> [[Gene ontology]] enrichment analysis reveals an association between progranulin and [[Notch signaling pathway|notch receptor]] signaling.<ref name="Paushter_2018" /> Granulin has also been shown to interact with Cyclin T1<ref name="pmid125889882">{{cite journal | vauthors = Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T | title = The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription | journal = Molecular and Cellular Biology | volume = 23 | issue = 5 | pages = 1688–702 | date = March 2003 | pmid = 12588988 | pmc = 151712 | doi = 10.1128/MCB.23.5.1688-1702.2003 }}</ref> and TRIB3.<u><ref name="pmid182761102">{{cite journal | vauthors = Zhou Y, Li L, Liu Q, Xing G, Kuai X, Sun J, Yin X, Wang J, Zhang L, He F | display-authors = 6  | title = E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3 | journal = Cellular Signalling | volume = 20 | issue = 5 | pages = 942–8 | date = May 2008 | pmid = 18276110 | doi = 10.1016/j.cellsig.2008.01.010 }}</ref></u>
| Homologene = 1577
 
| MGIid = 95832
== Function ==
| GeneAtlas_image1 = PBB_GE_GRN_211284_s_at_tn.png
 
  | GeneAtlas_image2 = PBB_GE_GRN_200678_x_at_tn.png
=== Development ===
| GeneAtlas_image3 = PBB_GE_GRN_216041_x_at_tn.png
Although progranulin expression increases as cells mature,<ref name="Petkau_2014" /> they are still involved in the development of multiple cell types. Progranulin is hypothesized to be a [[neurotrophic factor]] involved in [[Development of the human cortex|corticogenisis]]. Induced pluripotent stem cell lines (IPSC) harboring the GRN mutation show a decrease in cortical neuronal differentiation ability.<ref>{{cite journal | vauthors = Raitano S, Ordovàs L, De Muynck L, Guo W, Espuny-Camacho I, Geraerts M, Khurana S, Vanuytsel K, Tóth BI, Voets T, Vandenberghe R, Cathomen T, Van Den Bosch L, Vanderhaeghen P, Van Damme P, Verfaillie CM | display-authors = 6 | title = Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia | journal = Stem Cell Reports | volume = 4 | issue = 1 | pages = 16–24 | date = January 2015 | pmid = 25556567 | pmc = 4297877 | doi = 10.1016/j.stemcr.2014.12.001 }}</ref> A recent mice study suggests that progranulin may be involved in regulating the early development of [[cerebellar]] tissue by selecting for individual [[climbing fiber]]s as they intersect and form [[synapse]]s with [[Purkinje cell]]s.<ref>{{cite journal | vauthors = Uesaka N, Abe M, Konno K, Yamazaki M, Sakoori K, Watanabe T, Kao TH, Mikuni T, Watanabe M, Sakimura K, Kano M | display-authors = 6  | title = Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum | journal = Neuron | volume = 97 | issue = 4 | pages = 796–805.e5 | date = February 2018 | pmid = 29398357 | doi = 10.1016/j.neuron.2018.01.018 }}</ref> In addition, several studies implicate progranulin in [[synaptic pruning]], a microglial process that occurs during development of the neural network.<ref name="Lui_2016">{{cite journal | vauthors = Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC, Martens LH, Gao F, Coppola G, Sloan SA, Hsieh CL, Kim CC, Bigio EH, Weintraub S, Mesulam MM, Rademakers R, Mackenzie IR, Seeley WW, Karydas A, Miller BL, Borroni B, Ghidoni R, Farese RV, Paz JT, Barres BA, Huang EJ | display-authors = 6  | title = Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation | journal = Cell | volume = 165 | issue = 4 | pages = 921–35 | date = May 2016 | pmid = 27114033 | pmc = 4860138 | doi = 10.1016/j.cell.2016.04.001 }}</ref> [[Cytokine]]s, a neuronal marker for synapse elimination, is found to be upregulated in neurons with the GRN mutation.<ref name="Lui_2016" /> Increased cytokine tagging results in an increase in microglial density and activity around [[synapse]]s.<ref name="Lui_2016" /> Progranulin may also be involved in sexual determination during [[Embryonic stem cell|embryonic]] development.<ref name="Eriksen_2008" />
| Function = {{GNF_GO|id=GO:0005125 |text = cytokine activity}} {{GNF_GO|id=GO:0008083 |text = growth factor activity}}
 
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}}
=== Inflammation and wound healing ===
  | Process = {{GNF_GO|id=GO:0001835 |text = blastocyst hatching}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0007566 |text = embryo implantation}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0050679 |text = positive regulation of epithelial cell proliferation}}
Progranulin levels are elevated when tissue is inflamed. After wounding, [[keratinocyte]]s, [[macrophage]]s and [[neutrophil]]s increase production of progranulin.<ref name="Eriksen_2008" /> Neutrophils are capable of secreting [[elastase]] into the [[extracellular matrix]] that is capable of cleaving progranulin into granulin peptides, that promote further promote [[inflammation]].<ref name="Eriksen_2008" /> [[SLPI]], inhibitors of [[elastase]], are also released by neutrophiles and macrophages to modulate progranulin cleavage.<ref name="Eriksen_2008" /> Addition of granulin B in cultured [[epithelial]] cells causes cells to secrete [[Interleukin 8|IL-8]], a chemical that attracts [[monocyte]]s and neutrophils, which further suggests the involvement of granulin peptides in promoting [[inflammation]].<ref name="Eriksen_2008" /> The addition of exogenous [[SLPI]] and progranulin is able to alleviate the enhanced inflammatory response of mice that are unable to inhibit the cleavage of progranulin.<ref name="Eriksen_2008" />
  | Orthologs = {{GNF_Ortholog_box
 
    | Hs_EntrezGene = 2896
=== Cell proliferation ===
    | Hs_Ensembl = ENSG00000030582
Progranulin is highly expressed in cells that are highly proliferative in nature.<ref name="Eriksen_2008" /> Several studies implicate progranulin in [[tumorigenesis]] and neuronal outgrowth. Progranulin promotes [[mitogenesis]] in [[epithelial]] cultures.<ref name="Eriksen_2008" /> When two epithelial lines were cultured in media with recombinant PGRN, proliferation was stimulated.<ref name="Paushter_2018" /> Knockout of both progranulin homologues in a [[zebrafish]] model reduces [[axon]]al outgrowth.<ref name="Petkau_2014" /> In primary [[cortex (anatomy)|cortical]] and [[motor neuron]]s, progranulin regulates neuronal outgrowth and survival.<ref name="Petkau_2014" /> In primary motor neurons, progranulin has been shown to increase neurite outgrowth by regulating the [[GSK3B|glycogen synthase kinase-3 beta]].<ref name="Petkau_2014" /> Progranulin may function as an [[Autocrine signalling|autocrine]] growth factor in [[tumorigenesis]].<ref name="Nguyen_2013" />
    | Hs_RefseqProtein = NP_001012497
 
    | Hs_RefseqmRNA = NM_001012479
=== Lysosomal function ===
    | Hs_GenLoc_db =
 
    | Hs_GenLoc_chr = 17
The discovery of a GRN mutation leading to [[Lysosomal storage disease|lysosomal storage disorder]] led to many studies that explored progranulin's role in regulating protein homeostasis via the [[lysosomal]] pathway. Transcriptional gene network interference study suggests that progranulin is highly involved in lysosomal function and organization.<ref>{{cite journal | vauthors = Götzl JK, Lang CM, Haass C, Capell A | title = Impaired protein degradation in FTLD and related disorders | journal = Ageing Research Reviews | volume = 32 | pages = 122–139 | date = December 2016 | pmid = 27166223 | doi = 10.1016/j.arr.2016.04.008 }}</ref> Imaging studies have shown co-localization of progranulin and lysosomal marker [[LAMP1|LAMP-1]].<ref name="Kao_2017" /> Progranulin expression is regulated by [[TFEB]], a transcription factor that mediates proteins involved in lysosomal biosynthesis.<ref name="Kao_2017" /> Progranulin may be involved in regulating [[protease]] activity. Proteases that could be regulated by progranulin include prosaposin, which is cleaved into saposin peptides in the [[lysosome]], and [[cathepsin D]], the primary protease involved in protein aggregate break down.<ref name="Paushter_2018" /> GRN mutation shares similar neuropathology and clinical phenotype with [[CHMP2B]] and [[Valosin-containing protein|VCP]] mutations, genes that are both involved in the trafficking and breakdown of proteins involved in lysosomal function.<ref name="Eriksen_2008" />
    | Hs_GenLoc_start = 39778017
 
    | Hs_GenLoc_end = 39785996
== Clinical significance ==
    | Hs_Uniprot = P28799
 
    | Mm_EntrezGene = 14824
=== Frontal temporal dementia ===
    | Mm_Ensembl = ENSMUSG00000034708
[[Heterozygous]] mutation of the GRN gene leading to progranulin haploinsufficiency causes Frontal Temporal Dementia. <u><ref name="Mackenzie2007">{{cite journal | vauthors = Mackenzie IR | title = The neuropathology and clinical phenotype of FTD with progranulin mutations | journal = Acta Neuropathologica | volume = 114 | issue = 1 | pages = 49–54 | date = July 2007 | pmid = 17458552 | doi = 10.1007/s00401-007-0223-8 }}</ref><ref name="Baker2006">{{cite journal | vauthors = Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M | display-authors = 6 | title = Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 | journal = Nature | volume = 442 | issue = 7105 | pages = 916–9 | date = August 2006 | pmid = 16862116 | doi = 10.1038/nature05016 | bibcode = 2006Natur.442..916B }}</ref><ref name="Cruts_2006">{{cite journal | vauthors = Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C | display-authors = 6  | title = Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 | journal = Nature | volume = 442 | issue = 7105 | pages = 920–4 | date = August 2006 | pmid = 16862115 | doi = 10.1038/nature05017 | bibcode = 2006Natur.442..920C }}</ref></u> These mutations include [[frameshift]], [[splice site]], nonsense signal peptide, [[Kozak sequence]] disruptions and [[Missense mutation|missense]] mutations, which result in either [[nonsense-mediated decay]] or the production of non-functional protein.<ref name="Eriksen_2008" /> Patients with GRN caused FTD (GRN-FTD) exhibit asymmetric brain [[atrophy]], although age of onset, disease progression and clinical symptoms vary, suggesting that other genetic or environmental factors may be involved in disease expression.<ref name="Petkau_2014" /><ref name="Eriksen_2008" /> Pathological indicators include cytosolic [[ubiquitin]] deposits enriched in hyperphosphorylated [[TDP 43|TAR DNA Binding Protein (TDP-43)]], [[autophagy]]-related protein aggregates, ubiquitin-binding protein p62, [[Lentiform nucleus|lentiform]] intranuclear inclusions, dystrophic neurites and [[inflammation]].<ref name="Nguyen_2013" /><ref name="Eriksen_2008" /><ref name="Paushter_2018" /> Patients with the heterozygote mutation exhibit a reduction of 70-80% [[serum (blood)|serum]] progranulin levels when compared to controls.<ref name="Nguyen_2013" /> Reprogrammed stem cells restore GRN mRNA levels to 50%, further suggesting that some other genetic or environmental factor is involved in regulating FTD disease expression.<ref name="Nguyen_2013" /> Mice exhibit reduced [[autophagic]] flux and [[autophagy]]-dependent clearance.<ref name="Paushter_2018" /> Human FTLD-GRN derived [[fibroblast]]s show decrease lysosomal protease activity and [[lymphoblast]]s containing neuronal ceroid lipofuscinosis-like storage material.<ref name="Paushter_2018" /> FTLD-GRN IPSC cortical [[Neuron]]s have enlarged vesicles, [[lipofuscin]] accumulation and [[cathepsin D]] deficiency.<ref name="Paushter_2018" />
    | Mm_RefseqmRNA = XM_984981
 
    | Mm_RefseqProtein = XP_990075
=== Neuronal ceroid lipofuscinosis ===
    | Mm_GenLoc_db =
[[Zygosity|Homozygous]] mutation of the GRN gene causes [[neuronal ceroid lipofuscinosis]] (NCL) characterized by an accumulation of autofluorescent [[lipofuscin]], enlarged [[vacuole]]s, impairment in [[Lysosome|lysosomal]] activity, retinal & brain degeneration, exaggerated [[inflammation|inflammatory]] responses, microgliosis, astrogliosis and behavioral dysfunction such as [[Obsessive–compulsive disorder|OCD]]-like and disinhibition-like behavior.<ref name="Nguyen_2013" /><ref name="Paushter_2018" /> Aged GRN double mutant mice have [[lipofuscin]] deposits and enlarge [[lysosome]]s, while one group found phosphorylated [[TARDBP|TDP-43]].<ref name="Paushter_2018" />
    | Mm_GenLoc_chr = 11
 
    | Mm_GenLoc_start = 102246571
=== Other diseases ===
    | Mm_GenLoc_end = 102252895
Progranulin may also be involved in [[cancer]] development, [[atherosclerosis]] and [[Metabolic disorder|metabolic disease]]. Progranulin can promote [[cyclin D1]] expression in [[breast cancer]] lines and phosphorylation of proteins through extracellular regulated [[kinase]] signaling pathways.<ref name="Eriksen_2008" /> Progranulin is highly expressed in [[Ovary|ovarian]], [[Adrenocortical carcinoma|adrenal carcinomas]] and immortalized [[epithelial]] cells.<ref name="Eriksen_2008" /> There is a correlation between Progranulin concentration and [[cancer]] severity.<ref name="Paushter_2018" /> Granulin release by macrophages has been associated with fibrotic hepatic metastasis in pancreatic cancer.<ref>{{cite journal | vauthors = Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, Ireland L, Sakai T, Sakai K, Kim YS, Engle D, Campbell F, Palmer D, Ko JH, Tuveson DA, Hirsch E, Mielgo A, Schmid MC | display-authors = 6  | title = Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis | journal = Nature Cell Biology | volume = 18 | issue = 5 | pages = 549–60 | date = May 2016 | pmid = 27088855 | pmc = 4894551 | doi = 10.1038/ncb3340 }}</ref> The human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone.<u><ref name="pmid19816559">{{cite journal | vauthors = Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, Brindley PJ, Loukas A | display-authors = 6  | title = A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells | journal = PLoS Pathogens | volume = 5 | issue = 10 | pages = e1000611 | date = October 2009 | pmid = 19816559 | pmc = 2749447 | doi = 10.1371/journal.ppat.1000611 }}</ref></u> Progranulin may also be involved in promoting the progression of [[atherosclerosis]].<ref name="Nguyen_2013" /> While progranulin may be anti-atherogenic, granulins may be pro-atherogenic.<ref name="Nguyen_2013" /> Increased [[serum (blood)|serum]] and [[Blood plasma|plasma]] progranulin levels in patients with [[type 2 diabetes]] and visceral [[obesity]] implicating progranulin in [[Metabolic disorder|metabolic diseases]].<ref name="Nguyen_2013" />
    | Mm_Uniprot = Q3TVQ3
  }}
}}
'''Granulin''', also known as '''GRN''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GRN granulin| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2896| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== References ==
{{PBB_Summary
{{reflist|32em}}
| section_title =  
| summary_text = Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis.<ref name="entrez">{{cite web | title = Entrez Gene: GRN granulin| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2896| accessdate = }}</ref>
}}


==References==
== Further reading ==
{{reflist|2}}
{{refbegin|32em}}
==Further reading==
* {{cite journal | vauthors = Serrero G | title = Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player in breast cancer tumorigenesis | journal = Biochemical and Biophysical Research Communications | volume = 308 | issue = 3 | pages = 409–13 | date = August 2003 | pmid = 12914763 | doi = 10.1016/S0006-291X(03)01452-9 }}
{{refbegin | 2}}
* {{cite journal | vauthors = Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW | title = Progranulin in frontotemporal lobar degeneration and neuroinflammation | journal = Journal of Neuroinflammation | volume = 4 | issue =  | pages = 7 | date = February 2007 | pmid = 17291356 | pmc = 1805428 | doi = 10.1186/1742-2094-4-7 }}
*{{cite journal | author=Eriksen J, Mackenzie IR |title=Progranulin: normal function and role in neurodegeneration. |journal=J Neurochem |volume=104 |issue=2  |pages= 287-297 |year= 2008 |pmid= 117953663 |doi= 10.1111/j.14714159.2007.04968.x }}
* {{cite journal | vauthors = Pickering-Brown SM | title = Progranulin and frontotemporal lobar degeneration | journal = Acta Neuropathologica | volume = 114 | issue = 1 | pages = 39–47 | date = July 2007 | pmid = 17572900 | doi = 10.1007/s00401-007-0241-6 }}
{{PBB_Further_reading
* {{cite journal | vauthors = Bhandari V, Palfree RG, Bateman A | title = Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 5 | pages = 1715–9 | date = March 1992 | pmid = 1542665 | pmc = 48523 | doi = 10.1073/pnas.89.5.1715 | bibcode = 1992PNAS...89.1715B }}
| citations =
* {{cite journal | vauthors = Plowman GD, Green JM, Neubauer MG, Buckley SD, McDonald VL, Todaro GJ, Shoyab M | title = The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth | journal = The Journal of Biological Chemistry | volume = 267 | issue = 18 | pages = 13073–8 | date = June 1992 | pmid = 1618805 | doi =  }}
*{{cite journal  | author=Serrero G |title=Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player in breast cancer tumorigenesis. |journal=Biochem. Biophys. Res. Commun. |volume=308 |issue= 3 |pages= 409-13 |year= 2003 |pmid= 12914763 |doi= }}
* {{cite journal | vauthors = Bateman A, Belcourt D, Bennett H, Lazure C, Solomon S | title = Granulins, a novel class of peptide from leukocytes | journal = Biochemical and Biophysical Research Communications | volume = 173 | issue = 3 | pages = 1161–8 | date = December 1990 | pmid = 2268320 | doi = 10.1016/S0006-291X(05)80908-8 }}
*{{cite journal | author=Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW |title=Progranulin in frontotemporal lobar degeneration and neuroinflammation. |journal=Journal of neuroinflammation |volume=4 |issue=  |pages= 7 |year= 2007 |pmid= 17291356 |doi= 10.1186/1742-2094-4-7 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1-2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
*{{cite journal | author=Mackenzie IR |title=The neuropathology and clinical phenotype of FTD with progranulin mutations. |journal=Acta Neuropathol. |volume=114 |issue= 1 |pages= 49-54 |year= 2007 |pmid= 17458552 |doi= 10.1007/s00401-007-0223-8 }}
* {{cite journal | vauthors = Baba T, Hoff HB, Nemoto H, Lee H, Orth J, Arai Y, Gerton GL | title = Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells | journal = Molecular Reproduction and Development | volume = 34 | issue = 3 | pages = 233–43 | date = March 1993 | pmid = 8471244 | doi = 10.1002/mrd.1080340302 }}
*{{cite journal  | author=Pickering-Brown SM |title=Progranulin and frontotemporal lobar degeneration. |journal=Acta Neuropathol. |volume=114 |issue= 1 |pages= 39-47 |year= 2007 |pmid= 17572900 |doi= 10.1007/s00401-007-0241-6 }}
* {{cite journal | vauthors = Kardana A, Bagshawe KD, Coles B, Read D, Taylor M | title = Characterisation of UGP and its relationship with beta-core fragment | journal = British Journal of Cancer | volume = 67 | issue = 4 | pages = 686–92 | date = April 1993 | pmid = 8471426 | pmc = 1968365 | doi = 10.1038/bjc.1993.127 }}
*{{cite journal | author=Bhandari V, Bateman A |title=Structure and chromosomal location of the human granulin gene. |journal=Biochem. Biophys. Res. Commun. |volume=188 |issue= 1 |pages= 57-63 |year= 1992 |pmid= 1417868 |doi=  }}
* {{cite journal | vauthors = Zhou J, Gao G, Crabb JW, Serrero G | title = Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line | journal = The Journal of Biological Chemistry | volume = 268 | issue = 15 | pages = 10863–9 | date = May 1993 | pmid = 8496151 | doi =  }}
*{{cite journal  | author=Bhandari V, Palfree RG, Bateman A |title=Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 5 |pages= 1715-9 |year= 1992 |pmid= 1542665 |doi= }}
* {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = April 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
*{{cite journal | author=Plowman GD, Green JM, Neubauer MG, ''et al.'' |title=The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth. |journal=J. Biol. Chem. |volume=267 |issue= 18 |pages= 13073-8 |year= 1992 |pmid= 1618805 |doi=  }}
* {{cite journal | vauthors = Bhandari V, Daniel R, Lim PS, Bateman A | title = Structural and functional analysis of a promoter of the human granulin/epithelin gene | journal = The Biochemical Journal | volume = 319 ( Pt 2) | issue = 2 | pages = 441–7 | date = October 1996 | pmid = 8912679 | pmc = 1217788 | doi = 10.1042/bj3190441 }}
*{{cite journal | author=Bateman A, Belcourt D, Bennett H, ''et al.'' |title=Granulins, a novel class of peptide from leukocytes. |journal=Biochem. Biophys. Res. Commun. |volume=173 |issue= 3 |pages= 1161-8 |year= 1991 |pmid= 2268320 |doi= }}
* {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = April 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
*{{cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1-2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
*{{cite journal | author=Baba T, Hoff HB, Nemoto H, ''et al.'' |title=Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells. |journal=Mol. Reprod. Dev. |volume=34 |issue= 3 |pages= 233-43 |year= 1993 |pmid= 8471244 |doi= 10.1002/mrd.1080340302 }}
* {{cite journal | vauthors = Trinh DP, Brown KM, Jeang KT | title = Epithelin/granulin growth factors: extracellular cofactors for HIV-1 and HIV-2 Tat proteins | journal = Biochemical and Biophysical Research Communications | volume = 256 | issue = 2 | pages = 299–306 | date = March 1999 | pmid = 10079180 | doi = 10.1006/bbrc.1999.0317 }}
*{{cite journal | author=Kardana A, Bagshawe KD, Coles B, ''et al.'' |title=Characterisation of UGP and its relationship with beta-core fragment. |journal=Br. J. Cancer |volume=67 |issue= 4 |pages= 686-92 |year= 1993 |pmid= 8471426 |doi= }}
* {{cite journal | vauthors = He Z, Bateman A | title = Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo | journal = Cancer Research | volume = 59 | issue = 13 | pages = 3222–9 | date = July 1999 | pmid = 10397269 | doi =  }}
*{{cite journal | author=Zhou J, Gao G, Crabb JW, Serrero G |title=Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line. |journal=J. Biol. Chem. |volume=268 |issue= 15 |pages= 10863-9 |year= 1993 |pmid= 8496151 |doi=  }}
* {{cite journal | vauthors = Thornton MA, Poncz M, Korostishevsky M, Yakobson E, Usher S, Seligsohn U, Peretz H | title = The human platelet alphaIIb gene is not closely linked to its integrin partner beta3 | journal = Blood | volume = 94 | issue = 6 | pages = 2039–47 | date = September 1999 | pmid = 10477733 | doi =  }}
*{{cite journal | author=Andersson B, Wentland MA, Ricafrente JY, ''et al.'' |title=A "double adaptor" method for improved shotgun library construction. |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107-13 |year= 1996 |pmid= 8619474 |doi= 10.1006/abio.1996.0138 }}
*{{cite journal | author=Bhandari V, Daniel R, Lim PS, Bateman A |title=Structural and functional analysis of a promoter of the human granulin/epithelin gene. |journal=Biochem. J. |volume=319 ( Pt 2) |issue= |pages= 441-7 |year= 1996 |pmid= 8912679 |doi= }}
*{{cite journal | author=Yu W, Andersson B, Worley KC, ''et al.'' |title=Large-scale concatenation cDNA sequencing. |journal=Genome Res. |volume=7 |issue= 4 |pages= 353-8 |year= 1997 |pmid= 9110174 |doi= }}
*{{cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi= }}
*{{cite journal  | author=Zhang H, Serrero G |title=Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor). |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 24 |pages= 14202-7 |year= 1998 |pmid= 9826678 |doi=  }}
*{{cite journal | author=Trinh DP, Brown KM, Jeang KT |title=Epithelin/granulin growth factors: extracellular cofactors for HIV-1 and HIV-2 Tat proteins. |journal=Biochem. Biophys. Res. Commun. |volume=256 |issue= 2 |pages= 299-306 |year= 1999 |pmid= 10079180 |doi= 10.1006/bbrc.1999.0317 }}
*{{cite journal | author=He Z, Bateman A |title=Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo. |journal=Cancer Res. |volume=59 |issue= 13 |pages= 3222-9 |year= 1999 |pmid= 10397269 |doi=  }}
*{{cite journal | author=Thornton MA, Poncz M, Korostishevsky M, ''et al.'' |title=The human platelet alphaIIb gene is not closely linked to its integrin partner beta3. |journal=Blood |volume=94 |issue= 6 |pages= 2039-47 |year= 1999 |pmid= 10477733 |doi=  }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
== External links ==
{{WikiDoc Sources}}
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ftd-grn  GeneReviews/NCBI/NIH/UW entry on GRN-Related Frontotemporal Dementia]
 
{{PDB Gallery|geneid=2896}}
 
[[Category:Protein families]]
[[Category:Precursor proteins]]

Latest revision as of 19:59, 22 October 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
Granulin
File:PDB 1g26 EBI.jpg
the solution structure of a well-folded peptide based on the 31-residue amino-terminal subdomain of human granulin a
Identifiers
SymbolGranulin
PfamPF00396
InterProIPR000118
PROSITEPDOC00634
SCOP1pcn
SUPERFAMILY1pcn

Granulin is a protein that in humans is encoded by the GRN gene.[1][2][3] Each granulin protein is cleaved from the precursor progranulin, a 593 amino acid long and 68.5 kDa protein.[4] While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.

Progranulin

Progranulin is the precursor protein for granulin. Cleavage of progranulin produces a variety of active 6 kDa granulin peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Cleavage of progranulin into granulin occurs either in the extracellular matrix or the lysosome. Elastase, proteinase 3 and matrix metalloproteinase are proteases capable of cleaving progranulin into individual granulin peptides.[4][5] Progranulin and granulin can be further differentiated by their hypothesized opposing roles in the cell. While progranulin is associated with anti-inflammation, cleaved granulin peptides have been implicated in pro-inflammatory behavior. A C. elegans study showed that granulin peptides may also participate in toxic activity.[5]

Expression

Progranulin is expressed in a wide variety of cell types both in the periphery and in the central nervous system. Progranulin expression is low in early development, but increases as cells mature.[6] Cell types expressing progranulin include neurons, microglia, astrocytes and endothelial cells.[7] Progranulin has been found to be highly expressed in microglia and up-regulated during injury[7][6] Within the brain, progranulin mRNA is highly expressed in pyramidal, hippocampal and Purkinje cells cells.[4]

Structure

Each individual granulin domain peptide is 60 amino acids in length. Granulin peptides are cysteine rich and capable of forming 6 disulfide bonds per residue.[5] The disulfide bonds form a central rod-like core that shuttles each individual granulin peptide into a stacked β-sheet configuration.[7][4] The structure of the granulin protein is similar to the structure of proteins from protein families that consist of hormones, growth factors, ion channel modulators and enzyme inhibitors.[7] Because of progranulin's structural similarities to these proteins, much research was done to interrogate progranulin's potential role as a growth factor. When progranulin is secreted into the extracellular matrix, it is often glycosylated at 4 confirmed and 1 tentative N-linked glycosylation sites.[7][5] The n-terminus of progranulin is hypothesized to be involved in the secretion of progranulin via secretory vesicles.[7] Specifically, Progranulin may be involved in regulating exosome excretion.[8] The C-terminus of progranulin is hypothesized to be the primary binding partner of SORT1, a receptor of extracellular progranulin.[9][7] The structural differences between each individual granulin peptide have yet to be characterized.

Interactive partners

In the extracellular matrix, progranulin binds to receptors on several cell types resulting in either activation of a signal transduction pathway or engulfment into the cell. Several studies have shown progranulin's involvement in the binding of SORT1 and the subsequent trafficking of bounded progranulin to the lysosome.[7] One recent study has shown that progranulin may actually mediate prosaposin trafficking to the lysosome via SORT1.[10] However, the absence of SORT1 does not prevent exogenous progranulin from promoting neurite outgrowth or enhancing cell survival of GRN knockout cells, suggesting that other receptors are involved in mediating extracellular progranulin function[11] For example, SORT1 -/- neuronal cells are still able to bind progranulin.[11] Other studies have suggested tumor necrosis factor and EPH receptor A2 as potential progranulin facilitators.[7] After binding to the receptor, progranulin may induce and modulate signaling pathways such as MAPK/ERK, PI3K/Akt, and FAK.[5][11] Gene ontology enrichment analysis reveals an association between progranulin and notch receptor signaling.[5] Granulin has also been shown to interact with Cyclin T1[12] and TRIB3.[13]

Function

Development

Although progranulin expression increases as cells mature,[6] they are still involved in the development of multiple cell types. Progranulin is hypothesized to be a neurotrophic factor involved in corticogenisis. Induced pluripotent stem cell lines (IPSC) harboring the GRN mutation show a decrease in cortical neuronal differentiation ability.[14] A recent mice study suggests that progranulin may be involved in regulating the early development of cerebellar tissue by selecting for individual climbing fibers as they intersect and form synapses with Purkinje cells.[15] In addition, several studies implicate progranulin in synaptic pruning, a microglial process that occurs during development of the neural network.[16] Cytokines, a neuronal marker for synapse elimination, is found to be upregulated in neurons with the GRN mutation.[16] Increased cytokine tagging results in an increase in microglial density and activity around synapses.[16] Progranulin may also be involved in sexual determination during embryonic development.[4]

Inflammation and wound healing

Progranulin levels are elevated when tissue is inflamed. After wounding, keratinocytes, macrophages and neutrophils increase production of progranulin.[4] Neutrophils are capable of secreting elastase into the extracellular matrix that is capable of cleaving progranulin into granulin peptides, that promote further promote inflammation.[4] SLPI, inhibitors of elastase, are also released by neutrophiles and macrophages to modulate progranulin cleavage.[4] Addition of granulin B in cultured epithelial cells causes cells to secrete IL-8, a chemical that attracts monocytes and neutrophils, which further suggests the involvement of granulin peptides in promoting inflammation.[4] The addition of exogenous SLPI and progranulin is able to alleviate the enhanced inflammatory response of mice that are unable to inhibit the cleavage of progranulin.[4]

Cell proliferation

Progranulin is highly expressed in cells that are highly proliferative in nature.[4] Several studies implicate progranulin in tumorigenesis and neuronal outgrowth. Progranulin promotes mitogenesis in epithelial cultures.[4] When two epithelial lines were cultured in media with recombinant PGRN, proliferation was stimulated.[5] Knockout of both progranulin homologues in a zebrafish model reduces axonal outgrowth.[6] In primary cortical and motor neurons, progranulin regulates neuronal outgrowth and survival.[6] In primary motor neurons, progranulin has been shown to increase neurite outgrowth by regulating the glycogen synthase kinase-3 beta.[6] Progranulin may function as an autocrine growth factor in tumorigenesis.[11]

Lysosomal function

The discovery of a GRN mutation leading to lysosomal storage disorder led to many studies that explored progranulin's role in regulating protein homeostasis via the lysosomal pathway. Transcriptional gene network interference study suggests that progranulin is highly involved in lysosomal function and organization.[17] Imaging studies have shown co-localization of progranulin and lysosomal marker LAMP-1.[7] Progranulin expression is regulated by TFEB, a transcription factor that mediates proteins involved in lysosomal biosynthesis.[7] Progranulin may be involved in regulating protease activity. Proteases that could be regulated by progranulin include prosaposin, which is cleaved into saposin peptides in the lysosome, and cathepsin D, the primary protease involved in protein aggregate break down.[5] GRN mutation shares similar neuropathology and clinical phenotype with CHMP2B and VCP mutations, genes that are both involved in the trafficking and breakdown of proteins involved in lysosomal function.[4]

Clinical significance

Frontal temporal dementia

Heterozygous mutation of the GRN gene leading to progranulin haploinsufficiency causes Frontal Temporal Dementia. [18][19][20] These mutations include frameshift, splice site, nonsense signal peptide, Kozak sequence disruptions and missense mutations, which result in either nonsense-mediated decay or the production of non-functional protein.[4] Patients with GRN caused FTD (GRN-FTD) exhibit asymmetric brain atrophy, although age of onset, disease progression and clinical symptoms vary, suggesting that other genetic or environmental factors may be involved in disease expression.[6][4] Pathological indicators include cytosolic ubiquitin deposits enriched in hyperphosphorylated TAR DNA Binding Protein (TDP-43), autophagy-related protein aggregates, ubiquitin-binding protein p62, lentiform intranuclear inclusions, dystrophic neurites and inflammation.[11][4][5] Patients with the heterozygote mutation exhibit a reduction of 70-80% serum progranulin levels when compared to controls.[11] Reprogrammed stem cells restore GRN mRNA levels to 50%, further suggesting that some other genetic or environmental factor is involved in regulating FTD disease expression.[11] Mice exhibit reduced autophagic flux and autophagy-dependent clearance.[5] Human FTLD-GRN derived fibroblasts show decrease lysosomal protease activity and lymphoblasts containing neuronal ceroid lipofuscinosis-like storage material.[5] FTLD-GRN IPSC cortical Neurons have enlarged vesicles, lipofuscin accumulation and cathepsin D deficiency.[5]

Neuronal ceroid lipofuscinosis

Homozygous mutation of the GRN gene causes neuronal ceroid lipofuscinosis (NCL) characterized by an accumulation of autofluorescent lipofuscin, enlarged vacuoles, impairment in lysosomal activity, retinal & brain degeneration, exaggerated inflammatory responses, microgliosis, astrogliosis and behavioral dysfunction such as OCD-like and disinhibition-like behavior.[11][5] Aged GRN double mutant mice have lipofuscin deposits and enlarge lysosomes, while one group found phosphorylated TDP-43.[5]

Other diseases

Progranulin may also be involved in cancer development, atherosclerosis and metabolic disease. Progranulin can promote cyclin D1 expression in breast cancer lines and phosphorylation of proteins through extracellular regulated kinase signaling pathways.[4] Progranulin is highly expressed in ovarian, adrenal carcinomas and immortalized epithelial cells.[4] There is a correlation between Progranulin concentration and cancer severity.[5] Granulin release by macrophages has been associated with fibrotic hepatic metastasis in pancreatic cancer.[21] The human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone.[22] Progranulin may also be involved in promoting the progression of atherosclerosis.[11] While progranulin may be anti-atherogenic, granulins may be pro-atherogenic.[11] Increased serum and plasma progranulin levels in patients with type 2 diabetes and visceral obesity implicating progranulin in metabolic diseases.[11]

References

  1. ↑ Bhandari V, Bateman A (October 1992). "Structure and chromosomal location of the human granulin gene". Biochemical and Biophysical Research Communications. 188 (1): 57–63. doi:10.1016/0006-291X(92)92349-3. PMID 1417868.
  2. ↑ Zhang H, Serrero G (November 1998). "Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor)". Proceedings of the National Academy of Sciences of the United States of America. 95 (24): 14202–7. Bibcode:1998PNAS...9514202Z. doi:10.1073/pnas.95.24.14202. PMC 24351. PMID 9826678.
  3. ↑ "Entrez Gene: GRN granulin".
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 Eriksen JL, Mackenzie IR (January 2008). "Progranulin: normal function and role in neurodegeneration". Journal of Neurochemistry. 104 (2): 287–97. doi:10.1111/j.1471-4159.2007.04968.x. PMID 17953663.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 Paushter DH, Du H, Feng T, Hu F (May 2018). "The lysosomal function of progranulin, a guardian against neurodegeneration". Acta Neuropathologica: 1–17. doi:10.1007/s00401-018-1861-8. PMID 29744576.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Petkau TL, Leavitt BR (July 2014). "Progranulin in neurodegenerative disease". Trends in Neurosciences. 37 (7): 388–98. doi:10.1016/j.tins.2014.04.003. PMID 24800652.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 Kao AW, McKay A, Singh PP, Brunet A, Huang EJ (June 2017). "Progranulin, lysosomal regulation and neurodegenerative disease". Nature Reviews. Neuroscience. 18 (6): 325–333. doi:10.1038/nrn.2017.36. PMID 28435163.
  8. ↑ Benussi L, Ciani M, Tonoli E, Morbin M, Palamara L, Albani D, et al. (April 2016). "Loss of exosomes in progranulin-associated frontotemporal dementia". Neurobiology of Aging. 40: 41–49. doi:10.1016/j.neurobiolaging.2016.01.001. PMID 26973102.
  9. ↑ Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, et al. (November 2010). "Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin". Neuron. 68 (4): 654–67. doi:10.1016/j.neuron.2010.09.034. PMC 2990962. PMID 21092856.
  10. ↑ Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, et al. (May 2017). "Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations". Nature Communications. 8: 15277. Bibcode:2017NatCo...815277Z. doi:10.1038/ncomms15277. PMC 5477518. PMID 28541286.
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 Nguyen AD, Nguyen TA, Martens LH, Mitic LL, Farese RV (December 2013). "Progranulin: at the interface of neurodegenerative and metabolic diseases". Trends in Endocrinology and Metabolism. 24 (12): 597–606. doi:10.1016/j.tem.2013.08.003. PMC 3842380. PMID 24035620.
  12. ↑ Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T (March 2003). "The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription". Molecular and Cellular Biology. 23 (5): 1688–702. doi:10.1128/MCB.23.5.1688-1702.2003. PMC 151712. PMID 12588988.
  13. ↑ Zhou Y, Li L, Liu Q, Xing G, Kuai X, Sun J, et al. (May 2008). "E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3". Cellular Signalling. 20 (5): 942–8. doi:10.1016/j.cellsig.2008.01.010. PMID 18276110.
  14. ↑ Raitano S, Ordovàs L, De Muynck L, Guo W, Espuny-Camacho I, Geraerts M, et al. (January 2015). "Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia". Stem Cell Reports. 4 (1): 16–24. doi:10.1016/j.stemcr.2014.12.001. PMC 4297877. PMID 25556567.
  15. ↑ Uesaka N, Abe M, Konno K, Yamazaki M, Sakoori K, Watanabe T, et al. (February 2018). "Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum". Neuron. 97 (4): 796–805.e5. doi:10.1016/j.neuron.2018.01.018. PMID 29398357.
  16. ↑ 16.0 16.1 16.2 Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, et al. (May 2016). "Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation". Cell. 165 (4): 921–35. doi:10.1016/j.cell.2016.04.001. PMC 4860138. PMID 27114033.
  17. ↑ Götzl JK, Lang CM, Haass C, Capell A (December 2016). "Impaired protein degradation in FTLD and related disorders". Ageing Research Reviews. 32: 122–139. doi:10.1016/j.arr.2016.04.008. PMID 27166223.
  18. ↑ Mackenzie IR (July 2007). "The neuropathology and clinical phenotype of FTD with progranulin mutations". Acta Neuropathologica. 114 (1): 49–54. doi:10.1007/s00401-007-0223-8. PMID 17458552.
  19. ↑ Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. (August 2006). "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17". Nature. 442 (7105): 916–9. Bibcode:2006Natur.442..916B. doi:10.1038/nature05016. PMID 16862116.
  20. ↑ Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. (August 2006). "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21". Nature. 442 (7105): 920–4. Bibcode:2006Natur.442..920C. doi:10.1038/nature05017. PMID 16862115.
  21. ↑ Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, et al. (May 2016). "Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis". Nature Cell Biology. 18 (5): 549–60. doi:10.1038/ncb3340. PMC 4894551. PMID 27088855.
  22. ↑ Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, et al. (October 2009). "A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells". PLoS Pathogens. 5 (10): e1000611. doi:10.1371/journal.ppat.1000611. PMC 2749447. PMID 19816559.

Further reading

External links

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