Granulin

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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]

Structure

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 prostate cancer (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.

Function

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.[3]

Clinical significance

The human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone.[4]

Mutations in the GRN gene have been implicated in up to 25% of frontotemporal lobar degeneration, inherited in an autosomal dominant fashion with high penetrance.[5] Several loss-of-function mutations disease-causing mutations in GRN have been identified.[6][7]

Granulin release by macrophages has been associated with fibrotic hepatic metastasis in pancreatic cancer.[8]

Mutations in this gene have been associated with hereditary spastic paraplegia.[9]

Interactions

Granulin has been shown to interact with Cyclin T1[10] and TRIB3.[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. ↑ 3.0 3.1 "Entrez Gene: GRN granulin".
  4. ↑ Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, Brindley PJ, Loukas A (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.
  5. ↑ 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.
  6. ↑ 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 (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.
  7. ↑ 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 (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.
  8. ↑ 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 (May 2016). "Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis". Nature Cell Biology. 18 (5): 549–60. doi:10.1038/ncb3340. PMID 27088855.
  9. ↑ Faber I, Prota JR, Martinez AR, Lopes-Cendes I, França MC (January 2017). "A new phenotype associated with homozygous GRN mutations: complicated spastic paraplegia". European Journal of Neurology. 24 (1): e3–e4. doi:10.1111/ene.13194. PMID 28000352.
  10. ↑ 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.
  11. ↑ Zhou Y, Li L, Liu Q, Xing G, Kuai X, Sun J, Yin X, Wang J, Zhang L, He F (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.

Further reading

External links

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