PI4K2A: Difference between revisions

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{{Infobox_gene}}
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'''Phosphatidylinositol 4-kinase 2-alpha''' is an [[enzyme]] that in humans is encoded by the ''PI4K2A'' [[gene]].<ref name="pmid11244087">{{cite journal |vauthors=Barylko B, Gerber SH, Binns DD, Grichine N, Khvotchev M, Sudhof TC, Albanesi JP | title = A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans | journal = J Biol Chem | volume = 276 | issue = 11 | pages = 7705–8 |date=May 2001 | pmid = 11244087 | pmc =  | doi = 10.1074/jbc.C000861200 }}</ref><ref name="pmid11279162">{{cite journal |vauthors=Minogue S, Anderson JS, Waugh MG, dos Santos M, Corless S, Cramer R, Hsuan JJ | title = Cloning of a human type II phosphatidylinositol 4-kinase reveals a novel lipid kinase family | journal = J Biol Chem | volume = 276 | issue = 20 | pages = 16635–40 |date=May 2001 | pmid = 11279162 | pmc =  | doi = 10.1074/jbc.M100982200 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PI4KII phosphatidylinositol 4-kinase type II| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55361| accessdate = }}</ref>
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== Classification ==
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This [[gene]] encodes a [[1-phosphatidylinositol 4-kinase|phosphatidylinositol 4-kinase]] which [[catalysis|catalyzes]] [[phosphorylation]] of [[phosphatidylinositol]] at the D-4 position, yielding [[phosphatidylinositol 4-phosphate]] (PI4P). Besides the fact, that [[phosphatidylinositol 4-phosphate|PI4P]] serves as a precursor for other important phosphoinositides, such as [[phosphatidylinositol 4,5-bisphosphate]], [[phosphatidylinositol 4-phosphate|PI4P]] is an essential molecule in the [[cell signaling|cellular signaling]] and trafficking especially in the [[Golgi apparatus]] and the ''trans'' Golgi network.
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[[1-phosphatidylinositol 4-kinase|Phosphatidylinositol 4-kinases]] are evolutionary conserved among [[eukaryote]]s and include four human [[protein isoform|isoforms]]
* [[PI4KA|phosphatidylinositol 4-kinase alpha]] (PI4KA)
* [[PI4KB|phosphatidylinositol 4-kinase beta]] (PI4KB)
* phosphatidylinositol 4-kinase 2-alpha (PI4K2A)
* [[PI4K2B|phosphatidylinositol 4-kinase 2-beta]] (PI4K2B)
 
== Function ==
 
'''Phosphatidylinositol 4-kinase 2-alpha (PI4K2A)''' is the most abundant [[1-phosphatidylinositol 4-kinase|phosphatidylinositol 4-kinase]] in human cells and is responsible for the synthesis of approximately 50% of the total [[phosphatidylinositol 4-phosphate|PI4P]] within the cell. PI4K2A is associated mainly with the membranes of the [[Golgi apparatus|''trans'' Golgi network]] and early and late [[endosome]]s;<ref>{{cite journal|last1=Balla|first1=A|last2=Tuymetova|first2=G|last3=Barshishat|first3=M|last4=Geiszt|first4=M|last5=Balla|first5=T|title=Characterization of type II phosphatidylinositol 4-kinase isoforms reveals association of the enzymes with endosomal vesicular compartments.|journal=The Journal of Biological Chemistry|date=31 May 2002|volume=277|issue=22|pages=20041–50|pmid=11923287|doi=10.1074/jbc.m111807200}}</ref> its membrane association is achieved by a heavy [[palmitoylation]] within a specific [[cysteine]]-rich motif.<ref>{{cite journal|last1=Barylko|first1=B|last2=Mao|first2=YS|last3=Wlodarski|first3=P|last4=Jung|first4=G|last5=Binns|first5=DD|last6=Sun|first6=HQ|last7=Yin|first7=HL|last8=Albanesi|first8=JP|title=Palmitoylation controls the catalytic activity and subcellular distribution of phosphatidylinositol 4-kinase II{alpha}.|journal=The Journal of Biological Chemistry|date=10 April 2009|volume=284|issue=15|pages=9994–10003|pmid=19211550|doi=10.1074/jbc.M900724200|pmc=2665123}}</ref> Besides the synthesis of [[phosphatidylinositol 4,5-bisphosphate]], PI4K2A is involved in various cell processes including membrane trafficking, regulation of endosomal sorting promoting target protein recruitment to [[endosome]]s or [[Golgi apparatus|''trans'' Golgi network]], or [[signal transduction]]. Particularly, it regulates e.g. targeting of [[clathrin]] adaptor complexes to the [[Golgi apparatus]],<ref>{{cite journal|last1=Wang|first1=YJ|last2=Wang|first2=J|last3=Sun|first3=HQ|last4=Martinez|first4=M|last5=Sun|first5=YX|last6=Macia|first6=E|last7=Kirchhausen|first7=T|last8=Albanesi|first8=JP|last9=Roth|first9=MG|last10=Yin|first10=HL|title=Phosphatidylinositol 4 phosphate regulates targeting of clathrin adaptor AP-1 complexes to the Golgi.|journal=Cell|date=8 August 2003|volume=114|issue=3|pages=299–310|pmid=12914695|doi=10.1016/s0092-8674(03)00603-2}}</ref> [[epidermal growth factor receptor|EGFR]] signaling,<ref>{{cite journal|last1=Minogue|first1=S|last2=Waugh|first2=MG|last3=De Matteis|first3=MA|last4=Stephens|first4=DJ|last5=Berditchevski|first5=F|last6=Hsuan|first6=JJ|title=Phosphatidylinositol 4-kinase is required for endosomal trafficking and degradation of the EGF receptor.|journal=Journal of Cell Science|date=1 February 2006|volume=119|issue=Pt 3|pages=571–81|pmid=16443754|doi=10.1242/jcs.02752}}</ref> or the [[Wnt signaling pathway]].<ref>{{cite journal|last1=Pan|first1=W|last2=Choi|first2=SC|last3=Wang|first3=H|last4=Qin|first4=Y|last5=Volpicelli-Daley|first5=L|last6=Swan|first6=L|last7=Lucast|first7=L|last8=Khoo|first8=C|last9=Zhang|first9=X|last10=Li|first10=L|last11=Abrams|first11=CS|last12=Sokol|first12=SY|last13=Wu|first13=D|title=Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation.|journal=Science|date=5 September 2008|volume=321|issue=5894|pages=1350–3|pmid=18772438|doi=10.1126/science.1160741|pmc=2532521}}</ref>
 
== Clinical significance ==
 
Dysfunction of PI4K2A may contribute to [[neoplasm|tumour growth]],<ref>{{cite journal|last1=Li|first1=J|last2=Lu|first2=Y|last3=Zhang|first3=J|last4=Kang|first4=H|last5=Qin|first5=Z|last6=Chen|first6=C|title=PI4KIIalpha is a novel regulator of tumor growth by its action on angiogenesis and HIF-1alpha regulation.|journal=Oncogene|date=29 April 2010|volume=29|issue=17|pages=2550–9|pmid=20154717|doi=10.1038/onc.2010.14}}</ref> [[spastic paraplegia]],<ref>{{cite journal|last1=Simons|first1=JP|last2=Al-Shawi|first2=R|last3=Minogue|first3=S|last4=Waugh|first4=MG|last5=Wiedemann|first5=C|last6=Evangelou|first6=S|last7=Loesch|first7=A|last8=Sihra|first8=TS|last9=King|first9=R|last10=Warner|first10=TT|last11=Hsuan|first11=JJ|title=Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=14 July 2009|volume=106|issue=28|pages=11535–9|pmid=19581584|doi=10.1073/pnas.0903011106|pmc=2710652}}</ref> [[Gaucher's disease]],<ref>{{cite journal|last1=Jović|first1=M|last2=Kean|first2=MJ|last3=Szentpetery|first3=Z|last4=Polevoy|first4=G|last5=Gingras|first5=AC|last6=Brill|first6=JA|last7=Balla|first7=T|title=Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase.|journal=Molecular Biology of the Cell|date=April 2012|volume=23|issue=8|pages=1533–45|pmid=22337770|doi=10.1091/mbc.E11-06-0553|pmc=3327330}}</ref> or [[Alzheimer's disease]].<ref>{{cite journal|last1=Wu|first1=B|last2=Kitagawa|first2=K|last3=Zhang|first3=NY|last4=Liu|first4=B|last5=Inagaki|first5=C|title=Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4-kinase activity.|journal=Journal of Neurochemistry|date=December 2004|volume=91|issue=5|pages=1164–70|pmid=15569259|doi=10.1111/j.1471-4159.2004.02805.x}}</ref>
 
== Structure ==


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
PI4K2A is composed of a [[proline]]-rich ''N''-terminal region and a [[kinase]] domain located ''C''-terminally. The [[proline]]-rich ''N''-terminal region contains physiologically important binding sites for a [[ubiquitin]] ligase Itch <ref>{{cite journal|last1=Mössinger|first1=Julia|last2=Wieffer|first2=Marnix|last3=Krause|first3=Eberhard|last4=Freund|first4=Christian|last5=Gerth|first5=Fabian|last6=Krauss|first6=Michael|last7=Haucke|first7=Volker|title=Phosphatidylinositol 4-kinase IIα function at endosomes is regulated by the ubiquitin ligase Itch|journal=EMBO Reports|date=13 November 2012|volume=13|issue=12|pages=1087–1094|pmid=23146885|doi=10.1038/embor.2012.164|pmc=3512407}}</ref> and [[clathrin]] adaptor complex 3,<ref>{{cite journal|last1=Craige|first1=B.|last2=Salazar|first2=G.|last3=Faundez|first3=V.|title=Phosphatidylinositol-4-Kinase Type II Alpha Contains an AP-3-sorting Motif and a Kinase Domain That Are Both Required for Endosome Traffic|journal=Molecular Biology of the Cell|date=1 April 2008|volume=19|issue=4|pages=1415–1426|pmid=18256276|doi=10.1091/mbc.E07-12-1239|pmc=2291421}}</ref> but is likely disordered and dispensable for the kinase activity.<ref>{{cite journal|last1=Barylko|first1=B|last2=Wlodarski|first2=P|last3=Binns|first3=DD|last4=Gerber|first4=SH|last5=Earnest|first5=S|last6=Sudhof|first6=TC|last7=Grichine|first7=N|last8=Albanesi|first8=JP|title=Analysis of the catalytic domain of phosphatidylinositol 4-kinase type II.|journal=The Journal of Biological Chemistry|date=15 November 2002|volume=277|issue=46|pages=44366–75|pmid=12215430|doi=10.1074/jbc.m203241200}}</ref> The [[kinase]] domain can be divided into ''N''-terminal and ''C''-terminal lobes with the [[adenosine triphosphate|ATP]] binding groove and putative [[phosphatidylinositol]] binding pocket in between. The ''C''-lobe of the [[kinase]] domain contains an additional lateral hydrophobic pocket with no distinct function assigned yet.<ref name="Boura">{{cite journal|last1=Baumlova|first1=A.|last2=Chalupska|first2=D.|last3=Rozycki|first3=B.|last4=Jovic|first4=M.|last5=Wisniewski|first5=E.|last6=Klima|first6=M.|last7=Dubankova|first7=A.|last8=Kloer|first8=D. P.|last9=Nencka|first9=R.|last10=Balla|first10=T.|last11=Boura|first11=E.|title=The crystal structure of the phosphatidylinositol 4-kinase II|journal=EMBO Reports|date=28 August 2014|volume=15|issue=10|pages=1085–1092|pmid=25168678|doi=10.15252/embr.201438841|pmc=4253849}}</ref><ref>{{cite journal|last1=Zhou|first1=Qiangjun|last2=Li|first2=Jiangmei|last3=Yu|first3=Hang|last4=Zhai|first4=Yujia|last5=Gao|first5=Zhen|last6=Liu|first6=Yanxin|last7=Pang|first7=Xiaoyun|last8=Zhang|first8=Lunfeng|last9=Schulten|first9=Klaus|last10=Sun|first10=Fei|last11=Chen|first11=Chang|title=Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα|journal=Nature Communications|date=28 March 2014|volume=5|pmid=24675427|doi=10.1038/ncomms4552|pages=3552|pmc=3974213}}</ref>
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Phosphatidylinositol 4-kinase type II
| HGNCid =
| Symbol = PI4KII
| AltSymbols =; DKFZP761G1923; RP11-548K23.6
| OMIM = 609763
| ECnumber =
| Homologene = 6239
| MGIid = 1934031
| GeneAtlas_image1 = PBB_GE_PI4KII_209345_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_PI4KII_209346_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_PI4KII_215134_at_tn.png
| Function = {{GNF_GO|id=GO:0000287 |text = magnesium ion binding}} {{GNF_GO|id=GO:0004430 |text = 1-phosphatidylinositol 4-kinase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0016301 |text = kinase activity}} {{GNF_GO|id=GO:0016773 |text = phosphotransferase activity, alcohol group as acceptor}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0045121 |text = lipid raft}}
| Process = {{GNF_GO|id=GO:0006661 |text = phosphatidylinositol biosynthetic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 55361
    | Hs_Ensembl = ENSG00000043822
    | Hs_RefseqProtein = NP_060895
    | Hs_RefseqmRNA = NM_018425
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 10
    | Hs_GenLoc_start = 99390433
    | Hs_GenLoc_end = 99426181
    | Hs_Uniprot =
    | Mm_EntrezGene = 84095
    | Mm_Ensembl = ENSMUSG00000025178
    | Mm_RefseqmRNA = XM_994576
    | Mm_RefseqProtein = XP_999670
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 42143746
    | Mm_GenLoc_end = 42175529
    | Mm_Uniprot =
  }}
}}
'''Phosphatidylinositol 4-kinase type II''', also known as '''PI4KII''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PI4KII phosphatidylinositol 4-kinase type II| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55361| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
[[Image:PI4K2A.png|thumb|325 px|'''Cartoon representation of the kinase domain of the phosphatidylinositol 4-kinase 2-alpha.''' N-lobe is colored in gold, C-lobe in aquamarine, ATP in the active site between the lobes in the stick representation. PDB code: 4PLA.<ref name="Boura" />]]
{{PBB_Summary
| section_title =
| summary_text = Phosphatidylinositolpolyphosphates (PtdInsPs) are centrally involved in many biologic processes, ranging from cell growth and organization of the actin cytoskeleton to endo- and exocytosis. PI4KII phosphorylates PtdIns at the D-4 position, an essential step in the biosynthesis of PtdInsPs (Barylko et al., 2001).[supplied by OMIM]<ref name="entrez">{{cite web | title = Entrez Gene: PI4KII phosphatidylinositol 4-kinase type II| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55361| accessdate = }}</ref>
}}


==References==
==References==
{{reflist|2}}
{{reflist}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin}}
{{PBB_Further_reading  
{{PBB_Further_reading  
| citations =  
| citations =  
*{{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|last1=Balla|first1=A|last2=Balla|first2=T|title=Phosphatidylinositol 4-kinases: old enzymes with emerging functions.|journal=Trends in Cell Biology|date=July 2006|volume=16|issue=7|pages=351–61|pmid=16793271|doi=10.1016/j.tcb.2006.05.003}}
*{{cite journal  | author=Berditchevski F, Tolias KF, Wong K, ''et al.'' |title=A novel link between integrins, transmembrane-4 superfamily proteins (CD63 and CD81), and phosphatidylinositol 4-kinase. |journal=J. Biol. Chem. |volume=272 |issue= 5 |pages= 2595-8 |year= 1997 |pmid= 9006891 |doi=  }}
*{{cite journal|last1=Balla|first1=T|title=Phosphoinositides: tiny lipids with giant impact on cell regulation.|journal=Physiological Reviews|date=July 2013|volume=93|issue=3|pages=1019–137|pmid=23899561|doi=10.1152/physrev.00028.2012|pmc=3962547}}
*{{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 book|last1=Minogue|first1=S|last2=Waugh|first2=MG|title=The phosphatidylinositol 4-kinases: don't call it a comeback|journal=Sub-cellular Biochemistry|date=2012|volume=58|pages=1–24|pmid=22403072|doi=10.1007/978-94-007-3012-0_1|series=Subcellular Biochemistry|isbn=978-94-007-3011-3}}
*{{cite journal  | author=Claas C, Stipp CS, Hemler ME |title=Evaluation of prototype transmembrane 4 superfamily protein complexes and their relation to lipid rafts. |journal=J. Biol. Chem. |volume=276 |issue= 11 |pages= 7974-84 |year= 2001 |pmid= 11113129 |doi= 10.1074/jbc.M008650200 }}
*{{cite journal|last1=Kutateladze|first1=TG|title=Translation of the phosphoinositide code by PI effectors.|journal=Nature Chemical Biology|date=July 2010|volume=6|issue=7|pages=507–13|pmid=20559318|doi=10.1038/nchembio.390|pmc=3182472}}
*{{cite journal | author=Barylko B, Gerber SH, Binns DD, ''et al.'' |title=A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans. |journal=J. Biol. Chem. |volume=276 |issue= 11 |pages= 7705-8 |year= 2001 |pmid= 11244087 |doi= 10.1074/jbc.C000861200 }}
*{{cite journal|last1=Tan|first1=J|last2=Brill|first2=JA|title=Cinderella story: PI4P goes from precursor to key signaling molecule.|journal=Critical Reviews in Biochemistry and Molecular Biology|date=2014|volume=49|issue=1|pages=33–58|pmid=24219382|doi=10.3109/10409238.2013.853024}}
*{{cite journal  | author=Minogue S, Anderson JS, Waugh MG, ''et al.'' |title=Cloning of a human type II phosphatidylinositol 4-kinase reveals a novel lipid kinase family. |journal=J. Biol. Chem. |volume=276 |issue= 20 |pages= 16635-40 |year= 2001 |pmid= 11279162 |doi= 10.1074/jbc.M100982200 }}
*{{cite journal  | author=Wei YJ, Sun HQ, Yamamoto M, ''et al.'' |title=Type II phosphatidylinositol 4-kinase beta is a cytosolic and peripheral membrane protein that is recruited to the plasma membrane and activated by Rac-GTP. |journal=J. Biol. Chem. |volume=277 |issue= 48 |pages= 46586-93 |year= 2003 |pmid= 12324459 |doi= 10.1074/jbc.M206860200 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal | author=Waugh MG, Minogue S, Anderson JS, ''et al.'' |title=Localization of a highly active pool of type II phosphatidylinositol 4-kinase in a p97/valosin-containing-protein-rich fraction of the endoplasmic reticulum. |journal=Biochem. J. |volume=373 |issue= Pt 1 |pages= 57-63 |year= 2003 |pmid= 12650639 |doi= 10.1042/BJ20030089 }}
*{{cite journal  | author=Wang YJ, Wang J, Sun HQ, ''et al.'' |title=Phosphatidylinositol 4 phosphate regulates targeting of clathrin adaptor AP-1 complexes to the Golgi. |journal=Cell |volume=114 |issue= 3 |pages= 299-310 |year= 2003 |pmid= 12914695 |doi=  }}
*{{cite journal  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
*{{cite journal  | author=Beausoleil SA, Jedrychowski M, Schwartz D, ''et al.'' |title=Large-scale characterization of HeLa cell nuclear phosphoproteins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130-5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 }}
}}
}}
{{refend}}
{{refend}}


{{protein-stub}}
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Latest revision as of 15:28, 16 November 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

Phosphatidylinositol 4-kinase 2-alpha is an enzyme that in humans is encoded by the PI4K2A gene.[1][2][3]

Classification

This gene encodes a phosphatidylinositol 4-kinase which catalyzes phosphorylation of phosphatidylinositol at the D-4 position, yielding phosphatidylinositol 4-phosphate (PI4P). Besides the fact, that PI4P serves as a precursor for other important phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate, PI4P is an essential molecule in the cellular signaling and trafficking especially in the Golgi apparatus and the trans Golgi network.

Phosphatidylinositol 4-kinases are evolutionary conserved among eukaryotes and include four human isoforms

Function

Phosphatidylinositol 4-kinase 2-alpha (PI4K2A) is the most abundant phosphatidylinositol 4-kinase in human cells and is responsible for the synthesis of approximately 50% of the total PI4P within the cell. PI4K2A is associated mainly with the membranes of the trans Golgi network and early and late endosomes;[4] its membrane association is achieved by a heavy palmitoylation within a specific cysteine-rich motif.[5] Besides the synthesis of phosphatidylinositol 4,5-bisphosphate, PI4K2A is involved in various cell processes including membrane trafficking, regulation of endosomal sorting promoting target protein recruitment to endosomes or trans Golgi network, or signal transduction. Particularly, it regulates e.g. targeting of clathrin adaptor complexes to the Golgi apparatus,[6] EGFR signaling,[7] or the Wnt signaling pathway.[8]

Clinical significance

Dysfunction of PI4K2A may contribute to tumour growth,[9] spastic paraplegia,[10] Gaucher's disease,[11] or Alzheimer's disease.[12]

Structure

PI4K2A is composed of a proline-rich N-terminal region and a kinase domain located C-terminally. The proline-rich N-terminal region contains physiologically important binding sites for a ubiquitin ligase Itch [13] and clathrin adaptor complex 3,[14] but is likely disordered and dispensable for the kinase activity.[15] The kinase domain can be divided into N-terminal and C-terminal lobes with the ATP binding groove and putative phosphatidylinositol binding pocket in between. The C-lobe of the kinase domain contains an additional lateral hydrophobic pocket with no distinct function assigned yet.[16][17]

File:PI4K2A.png
Cartoon representation of the kinase domain of the phosphatidylinositol 4-kinase 2-alpha. N-lobe is colored in gold, C-lobe in aquamarine, ATP in the active site between the lobes in the stick representation. PDB code: 4PLA.[16]

References

  1. ↑ Barylko B, Gerber SH, Binns DD, Grichine N, Khvotchev M, Sudhof TC, Albanesi JP (May 2001). "A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans". J Biol Chem. 276 (11): 7705–8. doi:10.1074/jbc.C000861200. PMID 11244087.
  2. ↑ Minogue S, Anderson JS, Waugh MG, dos Santos M, Corless S, Cramer R, Hsuan JJ (May 2001). "Cloning of a human type II phosphatidylinositol 4-kinase reveals a novel lipid kinase family". J Biol Chem. 276 (20): 16635–40. doi:10.1074/jbc.M100982200. PMID 11279162.
  3. ↑ "Entrez Gene: PI4KII phosphatidylinositol 4-kinase type II".
  4. ↑ Balla, A; Tuymetova, G; Barshishat, M; Geiszt, M; Balla, T (31 May 2002). "Characterization of type II phosphatidylinositol 4-kinase isoforms reveals association of the enzymes with endosomal vesicular compartments". The Journal of Biological Chemistry. 277 (22): 20041–50. doi:10.1074/jbc.m111807200. PMID 11923287.
  5. ↑ Barylko, B; Mao, YS; Wlodarski, P; Jung, G; Binns, DD; Sun, HQ; Yin, HL; Albanesi, JP (10 April 2009). "Palmitoylation controls the catalytic activity and subcellular distribution of phosphatidylinositol 4-kinase II{alpha}". The Journal of Biological Chemistry. 284 (15): 9994–10003. doi:10.1074/jbc.M900724200. PMC 2665123. PMID 19211550.
  6. ↑ Wang, YJ; Wang, J; Sun, HQ; Martinez, M; Sun, YX; Macia, E; Kirchhausen, T; Albanesi, JP; Roth, MG; Yin, HL (8 August 2003). "Phosphatidylinositol 4 phosphate regulates targeting of clathrin adaptor AP-1 complexes to the Golgi". Cell. 114 (3): 299–310. doi:10.1016/s0092-8674(03)00603-2. PMID 12914695.
  7. ↑ Minogue, S; Waugh, MG; De Matteis, MA; Stephens, DJ; Berditchevski, F; Hsuan, JJ (1 February 2006). "Phosphatidylinositol 4-kinase is required for endosomal trafficking and degradation of the EGF receptor". Journal of Cell Science. 119 (Pt 3): 571–81. doi:10.1242/jcs.02752. PMID 16443754.
  8. ↑ Pan, W; Choi, SC; Wang, H; Qin, Y; Volpicelli-Daley, L; Swan, L; Lucast, L; Khoo, C; Zhang, X; Li, L; Abrams, CS; Sokol, SY; Wu, D (5 September 2008). "Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation". Science. 321 (5894): 1350–3. doi:10.1126/science.1160741. PMC 2532521. PMID 18772438.
  9. ↑ Li, J; Lu, Y; Zhang, J; Kang, H; Qin, Z; Chen, C (29 April 2010). "PI4KIIalpha is a novel regulator of tumor growth by its action on angiogenesis and HIF-1alpha regulation". Oncogene. 29 (17): 2550–9. doi:10.1038/onc.2010.14. PMID 20154717.
  10. ↑ Simons, JP; Al-Shawi, R; Minogue, S; Waugh, MG; Wiedemann, C; Evangelou, S; Loesch, A; Sihra, TS; King, R; Warner, TT; Hsuan, JJ (14 July 2009). "Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons". Proceedings of the National Academy of Sciences of the United States of America. 106 (28): 11535–9. doi:10.1073/pnas.0903011106. PMC 2710652. PMID 19581584.
  11. ↑ Jović, M; Kean, MJ; Szentpetery, Z; Polevoy, G; Gingras, AC; Brill, JA; Balla, T (April 2012). "Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase". Molecular Biology of the Cell. 23 (8): 1533–45. doi:10.1091/mbc.E11-06-0553. PMC 3327330. PMID 22337770.
  12. ↑ Wu, B; Kitagawa, K; Zhang, NY; Liu, B; Inagaki, C (December 2004). "Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4-kinase activity". Journal of Neurochemistry. 91 (5): 1164–70. doi:10.1111/j.1471-4159.2004.02805.x. PMID 15569259.
  13. ↑ Mössinger, Julia; Wieffer, Marnix; Krause, Eberhard; Freund, Christian; Gerth, Fabian; Krauss, Michael; Haucke, Volker (13 November 2012). "Phosphatidylinositol 4-kinase IIα function at endosomes is regulated by the ubiquitin ligase Itch". EMBO Reports. 13 (12): 1087–1094. doi:10.1038/embor.2012.164. PMC 3512407. PMID 23146885.
  14. ↑ Craige, B.; Salazar, G.; Faundez, V. (1 April 2008). "Phosphatidylinositol-4-Kinase Type II Alpha Contains an AP-3-sorting Motif and a Kinase Domain That Are Both Required for Endosome Traffic". Molecular Biology of the Cell. 19 (4): 1415–1426. doi:10.1091/mbc.E07-12-1239. PMC 2291421. PMID 18256276.
  15. ↑ Barylko, B; Wlodarski, P; Binns, DD; Gerber, SH; Earnest, S; Sudhof, TC; Grichine, N; Albanesi, JP (15 November 2002). "Analysis of the catalytic domain of phosphatidylinositol 4-kinase type II". The Journal of Biological Chemistry. 277 (46): 44366–75. doi:10.1074/jbc.m203241200. PMID 12215430.
  16. ↑ 16.0 16.1 Baumlova, A.; Chalupska, D.; Rozycki, B.; Jovic, M.; Wisniewski, E.; Klima, M.; Dubankova, A.; Kloer, D. P.; Nencka, R.; Balla, T.; Boura, E. (28 August 2014). "The crystal structure of the phosphatidylinositol 4-kinase II". EMBO Reports. 15 (10): 1085–1092. doi:10.15252/embr.201438841. PMC 4253849. PMID 25168678.
  17. ↑ Zhou, Qiangjun; Li, Jiangmei; Yu, Hang; Zhai, Yujia; Gao, Zhen; Liu, Yanxin; Pang, Xiaoyun; Zhang, Lunfeng; Schulten, Klaus; Sun, Fei; Chen, Chang (28 March 2014). "Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα". Nature Communications. 5: 3552. doi:10.1038/ncomms4552. PMC 3974213. PMID 24675427.

Further reading


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