Cytoskeleton-associated protein 4 is a protein that in humans is encoded by the CKAP4gene.[1][2]
CKAP4 also historically known as CLIMP-63 (cytoskeleton-linking membrane protein 63), or just p63 (during the 90’s) 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]
CLIMP-63 was discovered in the early 90’s 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 90’s 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 [16][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).[16] 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.[8]
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.[13][22]
References
↑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 ( Pt 3) (3): 685–94. PMID8314870.
↑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 ( Pt 3): 671–83. PMID8314869.
↑ 10.010.1Razzaq 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.
↑ 11.011.1Gupta 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.
↑ 13.013.1Li 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.
↑Schweizer A, Rohrer J, Slot JW, Geuze HJ, Kornfeld S (June 1995). "Reassessment of the subcellular localization of p63". Journal of Cell Science. 108 ( Pt 6): 2477–85. PMID7673362.
↑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 (Pt 13): 2248–58. doi:10.1242/jcs.008979. PMID17567679.
↑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.
Further reading
Tuffy KM, Planey SB (2012). "Cytoskeleton-Associated Protein 4: Functions Beyond the Endoplasmic Reticulum in Physiology and Disease". ISRN Cell Biology. 2012. doi:10.5402/2012/142313.
Bates SR (2009). "P63 (CKAP4) as an SP-A receptor: implications for surfactant turnover". Cellular Physiology and Biochemistry. 25 (1): 41–54. doi:10.1159/000272062. PMID20054143.