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CKAP4

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CKAP4
Identifiers
AliasesCKAP4,CLIMP-63, ERGIC-63, p63, cytoskeleton-associated protein 4, cytoskeleton associated protein 4, CLIMP63
External IDsMGI:2444926;HomoloGene:4970;GeneCards:CKAP4;OMA:CKAP4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10970

216197

Ensembl

ENSG00000136026

ENSMUSG00000046841

UniProt

Q07065

Q8BMK4

RefSeq (mRNA)

NM_006825

NM_175451

RefSeq (protein)

NP_006816

NP_780660

Location (UCSC)Chr 12: 106.24 – 106.3 MbChr 10: 84.36 – 84.37 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cytoskeleton-associated protein 4is aproteinthat in humans is encoded by theCKAP4gene.[5][6]

CKAP4 also historically known asCLIMP-63 (cytoskeleton-linking membrane protein 63),or just p63 (during the 1990s) is an abundant type IItransmembrane proteinresiding predominantly in theendoplasmic reticulum(ER) of eukaryotic cells and encoded in higher vertebrates by the geneCKAP4.[7][8][9][10][11]

Discovery

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CLIMP-63 was discovered in the early 1990s as the mostS-palmitoylatedprotein duringmitosis,[12][13]Nevertheless, the effect of this modification to date remains unclear. CLIMP-63 was extensively studied during the 1990s by the group of Hans-Peter Hauri (University of Basel, CH) which has characterized CLIMP-63's life in the ER. More recently, different groups have also reported CLIMP-63's presence at theplasma membraneacting as a ligand-activated receptor.[14][15][16]CLIMP-63 has also now been described as a marker in different cancers.[17]

Localization, molecular functions and regulation

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CLIMP-63's cellular distribution has been assessed (and re-assessed) several times in the last two decades. The protein includes a cytosolic segment composed of positively charged amino acid (2–23) which might act as a preponderant motif for folding and ER localization.[18][19]Furthermore, CLIMP-63 was one of the first discoveredER-shaping proteins.[20]and is mostly known for participating in the generation and maintenance of the ER sheets[20][21]This is thought to occur after dimerization of CLIMP-63's luminalCOILED-COILdomains incis(two CLIMP-63 proteins of the same ER membrane layer) and/ortrans(between two different ER membrane layers, across the ER lumen).[20]Multimerization might in addition limit CLIMP-63's diffusion out of ER-sheets.[22]

CLIMP-63 was also shown to bind microtubules through its cytoplasmicdisorderedtail which might help anchoring the ER-sheets to the cytoskeleton. This is regulated byphosphorylationof at least three serine residues of CLIMP-63's cytosolic tail (S3, S17 and S19) as phosphorylation interferes with CLIMP-63'smicrotubulebinding capacity.[23]

In addition, CLIMP-63 can undergo anotherpost-translational modification,S-palmitoylation, on cysteine 100 of its cytoplasmic domain. So far only the palmitoyl-acyltransferaseZDHHC2has been identified as a potential regulator of CLIMP-63's palmitoylation but as ZDHHC2 resides mostly at the plasma membrane, supplementary investigations are needed.[24][25]The consequence of S-palmitoylation remain to be investigated but could play a role in the cell cycle as CLIMP-63's palmitoylation was reported to strongly increase during mitosis.[12]

Finally, CLIMP-63 has been shown by different groups to serve as a cell surface receptor for various extracellular ligands, in particular forsurfactant protein A(SP-A) in lungs alveoli,[15]tissue plasminogen activator(tPA) in vascular smooth muscle cells[14]and foranti-proliferative factor(APF) in bladder epithelial cells of patients withinterstitial cystitisdisorder.[16]

Diseases

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More recently, CLIMP-63 has been related to different types of cancer prognosis. Upregulation of CLIMP-63 is observed incholangio-cellularandhepatocellularcarcinoma and it correlates with lymph node metastasis appearance.[17][26]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000136026–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000046841–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Schweizer A, Rohrer J, Jenö P, DeMaio A, Buchman TG, Hauri HP (March 1993)."A reversibly palmitoylated resident protein (p63) of an ER-Golgi intermediate compartment is related to a circulatory shock resuscitation protein".Journal of Cell Science.104(3): 685–94.doi:10.1242/jcs.104.3.685.PMID8314870.
  6. ^"Entrez Gene: CKAP4 cytoskeleton-associated protein 4".
  7. ^"Gene: CKAP4 (ENSG00000136026) - Summary - Homo sapiens - Ensembl genome browser 89".may2017.archive.ensembl.org.Retrieved2018-03-26.
  8. ^"Gene: Ckap4 (ENSMUSG00000046841) - Summary - Mus musculus - Ensembl genome browser 89".may2017.archive.ensembl.org.Retrieved2018-03-26.
  9. ^pubmeddev."PubMed Links for Gene (Select 10970) - PubMed - NCBI".ncbi.nlm.nih.gov.Retrieved2018-03-26.
  10. ^pubmeddev."PubMed Links for Gene (Select 216197) - PubMed - NCBI".ncbi.nlm.nih.gov.Retrieved2018-03-26.
  11. ^"CKAP4 cytoskeleton associated protein 4 [Homo sapiens (human)] - Gene - NCBI".ncbi.nlm.nih.gov.Retrieved2018-03-26.
  12. ^abMundy DI, Warren G (January 1992)."Mitosis and inhibition of intracellular transport stimulate palmitoylation of a 62-kD protein".The Journal of Cell Biology.116(1): 135–46.doi:10.1083/jcb.116.1.135.PMC2289273.PMID1730740.
  13. ^Schweizer A, Ericsson M, Bächi T, Griffiths G, Hauri HP (March 1993). "Characterization of a novel 63 kDa membrane protein. Implications for the organization of the ER-to-Golgi pathway".Journal of Cell Science.104(3): 671–83.doi:10.1242/jcs.104.3.671.PMID8314869.
  14. ^abRazzaq TM, Bass R, Vines DJ, Werner F, Whawell SA, Ellis V (October 2003)."Functional regulation of tissue plasminogen activator on the surface of vascular smooth muscle cells by the type-II transmembrane protein p63 (CKAP4)".The Journal of Biological Chemistry.278(43): 42679–85.doi:10.1074/jbc.M305695200.PMID12913003.
  15. ^abGupta N, Manevich Y, Kazi AS, Tao JQ, Fisher AB, Bates SR (September 2006). "Identification and characterization of p63 (CKAP4/ERGIC-63/CLIMP-63), a surfactant protein A binding protein, on type II pneumocytes".American Journal of Physiology. Lung Cellular and Molecular Physiology.291(3): L436-46.doi:10.1152/ajplung.00415.2005.PMID16556726.S2CID24903427.
  16. ^abPlaney SL, Keay SK, Zhang CO, Zacharias DA (March 2009)."Palmitoylation of cytoskeleton associated protein 4 by DHHC2 regulates antiproliferative factor-mediated signaling".Molecular Biology of the Cell.20(5): 1454–63.doi:10.1091/mbc.E08-08-0849.PMC2649263.PMID19144824.
  17. ^abLi MH, Dong LW, Li SX, Tang GS, Pan YF, Zhang J, Wang H, Zhou HB, Tan YX, Hu HP, Wang HY (September 2013). "Expression of cytoskeleton-associated protein 4 is related to lymphatic metastasis and indicates prognosis of intrahepatic cholangiocarcinoma patients after surgery resection".Cancer Letters.337(2): 248–53.doi:10.1016/j.canlet.2013.05.003.PMID23665508.
  18. ^Schweizer A, Rohrer J, Hauri HP, Kornfeld S (July 1994)."Retention of p63 in an ER-Golgi intermediate compartment depends on the presence of all three of its domains and on its ability to form oligomers".The Journal of Cell Biology.126(1): 25–39.doi:10.1083/jcb.126.1.25.PMC2120087.PMID8027183.
  19. ^Schweizer A, Rohrer J, Slot JW, Geuze HJ, Kornfeld S (June 1995)."Reassessment of the subcellular localization of p63".Journal of Cell Science.108(6): 2477–85.doi:10.1242/jcs.108.6.2477.PMID7673362.
  20. ^abcKlopfenstein DR, Klumperman J, Lustig A, Kammerer RA, Oorschot V, Hauri HP (June 2001)."Subdomain-specific localization of CLIMP-63 (p63) in the endoplasmic reticulum is mediated by its luminal Alpha -helical segment".The Journal of Cell Biology.153(6): 1287–300.doi:10.1083/jcb.153.6.1287.PMC2192027.PMID11402071.
  21. ^Shibata Y, Shemesh T, Prinz WA, Palazzo AF, Kozlov MM, Rapoport TA (November 2010)."Mechanisms determining the morphology of the peripheral ER".Cell.143(5): 774–88.doi:10.1016/j.cell.2010.11.007.PMC3008339.PMID21111237.
  22. ^Nikonov AV, Hauri HP, Lauring B, Kreibich G (July 2007). "Climp-63-mediated binding of microtubules to the ER affects the lateral mobility of translocon complexes".Journal of Cell Science.120(13): 2248–58.doi:10.1242/jcs.008979.PMID17567679.S2CID6766979.
  23. ^Vedrenne C, Klopfenstein DR, Hauri HP (April 2005)."Phosphorylation controls CLIMP-63-mediated anchoring of the endoplasmic reticulum to microtubules".Molecular Biology of the Cell.16(4): 1928–37.doi:10.1091/mbc.E04-07-0554.PMC1073672.PMID15703217.
  24. ^Zhang J, Planey SL, Ceballos C, Stevens SM, Keay SK, Zacharias DA (July 2008)."Identification of CKAP4/p63 as a major substrate of the palmitoyl acyltransferase DHHC2, a putative tumor suppressor, using a novel proteomics method".Molecular & Cellular Proteomics.7(7): 1378–88.doi:10.1074/mcp.M800069-MCP200.PMC2493380.PMID18296695.
  25. ^Sandoz PA, van der Goot FG (April 2015)."How many lives does CLIMP-63 have?".Biochemical Society Transactions.43(2): 222–8.doi:10.1042/BST20140272.PMC4627503.PMID25849921.
  26. ^Li SX, Tang GS, Zhou DX, Pan YF, Tan YX, Zhang J, Zhang B, Ding ZW, Liu LJ, Jiang TY, Hu HP, Dong LW, Wang HY (May 2014)."Prognostic significance of cytoskeleton-associated membrane protein 4 and its palmitoyl acyltransferase DHHC2 in hepatocellular carcinoma".Cancer.120(10): 1520–31.doi:10.1002/cncr.28593.PMID24863391.S2CID37070876.

Further reading

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