CKAP4 explained

Cytoskeleton-associated protein 4 is a protein that in humans is encoded by the CKAP4 gene.[1] [2]

CKAP4 also historically known as CLIMP-63 (cytoskeleton-linking membrane protein 63), or just p63 (during the 1990s) is an abundant type II transmembrane protein residing predominantly in the endoplasmic reticulum (ER) of eukaryotic cells and encoded in higher vertebrates by the gene CKAP4.[3] [4] [5] [6] [7]

Discovery

CLIMP-63 was discovered in the early 1990s as the most S-palmitoylated protein during mitosis,[8] [9] 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 the plasma membrane acting as a ligand-activated receptor.[10] [11] [12] CLIMP-63 has also now been described as a marker in different cancers.[13]

Localization, molecular functions and regulation

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.[14] [15] Furthermore, CLIMP-63 was one of the first discovered ER-shaping proteins.[16] and is mostly known for participating in the generation and maintenance of the ER sheets [17] This is thought to occur after dimerization of CLIMP-63's luminal COILED-COIL domains in cis (two CLIMP-63 proteins of the same ER membrane layer) and/or trans (between two different ER membrane layers, across the ER lumen). Multimerization might in addition limit CLIMP-63's diffusion out of ER-sheets.[18]

CLIMP-63 was also shown to bind microtubules through its cytoplasmic disordered tail which might help anchoring the ER-sheets to the cytoskeleton. This is regulated by phosphorylation of at least three serine residues of CLIMP-63's cytosolic tail (S3, S17 and S19) as phosphorylation interferes with CLIMP-63's microtubule binding capacity.[19]

In addition, CLIMP-63 can undergo another post-translational modification, S-palmitoylation, on cysteine 100 of its cytoplasmic domain. So far only the palmitoyl-acyltransferase ZDHHC2 has been identified as a potential regulator of CLIMP-63's palmitoylation but as ZDHHC2 resides mostly at the plasma membrane, supplementary investigations are needed.[20] [21] 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.

Finally, CLIMP-63 has been shown by different groups to serve as a cell surface receptor for various extracellular ligands, in particular for surfactant protein A (SP-A) in lungs alveoli, tissue plasminogen activator (tPA) in vascular smooth muscle cells and for anti-proliferative factor (APF) in bladder epithelial cells of patients with interstitial cystitis disorder.

Diseases

More recently, CLIMP-63 has been related to different types of cancer prognosis. Upregulation of CLIMP-63 is observed in cholangio-cellular and hepatocellular carcinoma and it correlates with lymph node metastasis appearance.[22]

Further reading

Notes and References

  1. Schweizer A, Rohrer J, Jenö P, DeMaio A, Buchman TG, Hauri HP . 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 . March 1993 . 10.1242/jcs.104.3.685 . 8314870 .
  2. Web site: Entrez Gene: CKAP4 cytoskeleton-associated protein 4.
  3. Web site: Gene: CKAP4 (ENSG00000136026) - Summary - Homo sapiens - Ensembl genome browser 89. may2017.archive.ensembl.org. en-gb. 2018-03-26.
  4. Web site: Gene: Ckap4 (ENSMUSG00000046841) - Summary - Mus musculus - Ensembl genome browser 89. may2017.archive.ensembl.org. en-gb. 2018-03-26.
  5. Web site: PubMed Links for Gene (Select 10970) - PubMed - NCBI. pubmeddev. www.ncbi.nlm.nih.gov. 2018-03-26.
  6. Web site: PubMed Links for Gene (Select 216197) - PubMed - NCBI. pubmeddev. www.ncbi.nlm.nih.gov. 2018-03-26.
  7. Web site: CKAP4 cytoskeleton associated protein 4 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2018-03-26.
  8. Mundy DI, Warren G . Mitosis and inhibition of intracellular transport stimulate palmitoylation of a 62-kD protein . The Journal of Cell Biology . 116 . 1 . 135–46 . January 1992 . 1730740 . 2289273 . 10.1083/jcb.116.1.135.
  9. Schweizer A, Ericsson M, Bächi T, Griffiths G, Hauri HP . 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 . March 1993 . 10.1242/jcs.104.3.671 . 8314869 .
  10. Razzaq TM, Bass R, Vines DJ, Werner F, Whawell SA, Ellis V . 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 . October 2003 . 12913003 . 10.1074/jbc.M305695200 . free .
  11. Gupta N, Manevich Y, Kazi AS, Tao JQ, Fisher AB, Bates SR . 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 . September 2006 . 16556726 . 10.1152/ajplung.00415.2005 . 24903427 .
  12. Planey SL, Keay SK, Zhang CO, Zacharias DA . Palmitoylation of cytoskeleton associated protein 4 by DHHC2 regulates antiproliferative factor-mediated signaling . Molecular Biology of the Cell . 20 . 5 . 1454–63 . March 2009 . 19144824 . 2649263 . 10.1091/mbc.E08-08-0849 .
  13. Li MH, Dong LW, Li SX, Tang GS, Pan YF, Zhang J, Wang H, Zhou HB, Tan YX, Hu HP, Wang HY . 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 . September 2013 . 23665508 . 10.1016/j.canlet.2013.05.003 .
  14. Schweizer A, Rohrer J, Hauri HP, Kornfeld S . 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 . July 1994 . 8027183 . 2120087 . 10.1083/jcb.126.1.25.
  15. Schweizer A, Rohrer J, Slot JW, Geuze HJ, Kornfeld S . Reassessment of the subcellular localization of p63 . Journal of Cell Science . 108 . 6 . 2477–85 . June 1995 . 10.1242/jcs.108.6.2477 . 7673362 .
  16. Klopfenstein DR, Klumperman J, Lustig A, Kammerer RA, Oorschot V, Hauri HP . 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 . June 2001 . 11402071 . 2192027 . 10.1083/jcb.153.6.1287.
  17. Shibata Y, Shemesh T, Prinz WA, Palazzo AF, Kozlov MM, Rapoport TA . Mechanisms determining the morphology of the peripheral ER . Cell . 143 . 5 . 774–88 . November 2010 . 21111237 . 3008339 . 10.1016/j.cell.2010.11.007 .
  18. Nikonov AV, Hauri HP, Lauring B, Kreibich G . Climp-63-mediated binding of microtubules to the ER affects the lateral mobility of translocon complexes . Journal of Cell Science . 120 . 13 . 2248–58 . July 2007 . 17567679 . 10.1242/jcs.008979 . 6766979 .
  19. Vedrenne C, Klopfenstein DR, Hauri HP . Phosphorylation controls CLIMP-63-mediated anchoring of the endoplasmic reticulum to microtubules . Molecular Biology of the Cell . 16 . 4 . 1928–37 . April 2005 . 15703217 . 1073672 . 10.1091/mbc.E04-07-0554 .
  20. Zhang J, Planey SL, Ceballos C, Stevens SM, Keay SK, Zacharias DA . 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 . July 2008 . 18296695 . 2493380 . 10.1074/mcp.M800069-MCP200 . free .
  21. Sandoz PA, van der Goot FG . How many lives does CLIMP-63 have? . Biochemical Society Transactions . 43 . 2 . 222–8 . April 2015 . 25849921 . 4627503 . 10.1042/BST20140272 .
  22. 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 . Prognostic significance of cytoskeleton-associated membrane protein 4 and its palmitoyl acyltransferase DHHC2 in hepatocellular carcinoma . Cancer . 120 . 10 . 1520–31 . May 2014 . 24863391 . 10.1002/cncr.28593 . 37070876 . free .

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