CKAP4

CLIMP-63 was discovered in the early 1990s as the most S-palmitoylated protein during mitosis,[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 the plasma membrane acting as a ligand-activated receptor.[14][15][16] CLIMP-63 has also now been described as a marker in different cancers.[17]

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 discovered ER-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 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).[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 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.[23]

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.[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 for surfactant protein A (SP-A) in lungs alveoli,[15] tissue plasminogen activator (tPA) in vascular smooth muscle cells [14] and for anti-proliferative factor (APF) in bladder epithelial cells of patients with interstitial cystitis disorder.[16]

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.[17][26]

• Human CKAP4 genome location and CKAP4 gene details page in the UCSC Genome Browser.