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CKLF like MARVEL transmembrane domain-containing 4

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CKLF-like MARVEL transmembrane domain-containing protein 4
Identifiers
SymbolCMTM4
Alt. symbolsCKLFSF4
Alt. namesChemokine-like factor superfamily member 4
HGNC19175
OMIM607887
RefSeqNM_178818.3
UniProtQ8IZR5
Other data
LocusChr. 16 q21-q22.1
Search for
StructuresSwiss-model
DomainsInterPro

CKLF like MARVEL transmembrane domain-containing 4 (i.e. CMTM4), formerly termed chemokine-like factor superfamily 4 (i.e. CKLFSF4), is a small transmembrane protein which passes the plasma membrane four times. It has 3 known isoforms, the CMTM4-v1 to CMTM4-v3 proteins.[1] Protein isoforms are variant products that are made by alternative splicing of a single gene. The gene for the CMTM4 isoforms is located in band 22 on the long (i.e. "q") arm of chromosome 16.[2] The CMTM4 gene and its 3 isoform proteins belong to the CKLF-like MARVEL transmembrane domain-containing family of structurally and functionally related genes and proteins.[3] CMTM4-v1 and CMTM4-v2 are widely expressed in multiple human tissue while CMTM4-v3 has been detected only in the kidney and placental tissues.[4][5]

The Cancer Genome Atlas indicates that CMTM4 protein is frequently reduced in colorectal cancer and its high expression is associated with increased overall survival rates in individuals with this cancer.[6] CMTM4 protein was also found to be greatly reduced in the tissues of clear cell renal cell carcinoma compared to nearby normal renal (i.e. kidney) tissues and the forced overexpression of this protein in 786-O cells (a renal cancer cell line) inhibited their growth in culture as well as in a xenograph nude mouse model.[7] Finally, CMTM4 protein levels were lower in several brain cancers, such as glioblastomas,[7][8] neuroblastomas, and medulloblastomas, compared to their levels in nearby normal, non-tumorous brain tissues.[7][9] These studies suggest CMTM4 may act to suppress these malignancies. Further studies are needed to confirm these relationships and determine if CMTM4 protein can be used as a marker for the severity of these malignancies and/or serve as a therapeutic target for treating them.[4][9][10]

CMTM4 in IL-17A signaling

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Recently, CMTM4 has been identified to play a critical role in IL-17A signaling.[11] The IL-17 receptor consists of two subunits: IL-17 receptor subunit A and C (IL-17RA, IL-17RC).[12][13] CMTM4 was reported to be associated with the transmembrane domain of IL-17RC. This association proved to be critical for IL-17 signaling as CMTM4 knockout cells were unresponsive to IL-17A stimulation. Interestingly, lack of CMTM4 in cells caused an overall decrease in IL-17RC surface expression and impaired IL-17RC glycosylation. Altogether, CMTM4 regulates IL-17RC glycosylation status and its cellular localization.[11]

References

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  1. ^ Zhang W, Qi H, Mo X, Sun Q, Li T, Song Q, et al. (February 2017). "CMTM8 is Frequently Downregulated in Multiple Solid Tumors". Applied Immunohistochemistry & Molecular Morphology. 25 (2): 122–128. doi:10.1097/PAI.0000000000000274. PMID 26574634. S2CID 205912507.
  2. ^ Duan HJ, Li XY, Liu C, Deng XL (April 2020). "Chemokine-like factor-like MARVEL transmembrane domain-containing family in autoimmune diseases". Chinese Medical Journal. 133 (8): 951–958. doi:10.1097/CM9.0000000000000747. PMC 7176445. PMID 32195671.
  3. ^ Han W, Ding P, Xu M, Wang L, Rui M, Shi S, et al. (June 2003). "Identification of eight genes encoding chemokine-like factor superfamily members 1-8 (CKLFSF1-8) by in silico cloning and experimental validation". Genomics. 81 (6): 609–617. doi:10.1016/s0888-7543(03)00095-8. PMID 12782130.
  4. ^ a b Li M, Luo F, Tian X, Yin S, Zhou L, Zheng S (2020). "Chemokine-Like Factor-Like MARVEL Transmembrane Domain-Containing Family in Hepatocellular Carcinoma: Latest Advances". Frontiers in Oncology. 10: 595973. doi:10.3389/fonc.2020.595973. PMC 7691587. PMID 33282744.
  5. ^ Ge YY, Duan HJ, Deng XL (April 2021). "Possible effects of chemokine-like factor-like MARVEL transmembrane domain-containing family on antiphospholipid syndrome". Chinese Medical Journal. 134 (14): 1661–1668. doi:10.1097/CM9.0000000000001449. PMC 8318642. PMID 33813507.
  6. ^ Xue H, Li T, Wang P, Mo X, Zhang H, Ding S, et al. (September 2019). "CMTM4 inhibits cell proliferation and migration via AKT, ERK1/2, and STAT3 pathway in colorectal cancer". Acta Biochimica et Biophysica Sinica. 51 (9): 915–924. doi:10.1093/abbs/gmz084. PMID 31435638.
  7. ^ a b c Li T, Cheng Y, Wang P, Wang W, Hu F, Mo X, et al. (October 2015). "CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma". Journal of Experimental & Clinical Cancer Research. 34: 122. doi:10.1186/s13046-015-0236-4. PMC 4609138. PMID 26474560.
  8. ^ Delic S, Thuy A, Schulze M, Proescholdt MA, Dietrich P, Bosserhoff AK, Riemenschneider MJ (July 2015). "Systematic investigation of CMTM family genes suggests relevance to glioblastoma pathogenesis and CMTM1 and CMTM3 as priority targets". Genes, Chromosomes & Cancer. 54 (7): 433–443. doi:10.1002/gcc.22255. PMID 25931111. S2CID 25545349.
  9. ^ a b Wu J, Li L, Wu S, Xu B (August 2020). "CMTM family proteins 1-8: roles in cancer biological processes and potential clinical value". Cancer Biology & Medicine. 17 (3): 528–542. doi:10.20892/j.issn.2095-3941.2020.0032. PMC 7476098. PMID 32944388.
  10. ^ Liang Z, Xie J, Huang L, Huang Y, Zhang Y, Ma R, et al. (April 2021). "Comprehensive analysis of the prognostic value of the chemokine-like factor-like MARVEL transmembrane domain-containing family in gastric cancer". Journal of Gastrointestinal Oncology. 12 (2): 388–406. doi:10.21037/jgo-21-78. PMC 8107618. PMID 34012634.
  11. ^ a b Knizkova D, Pribikova M, Draberova H, Semberova T, Trivic T, Synackova A, et al. (November 2022). "CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology". Nature Immunology. 23 (11): 1644–1652. doi:10.1038/s41590-022-01325-9. PMC 9663306. PMID 36271145.
  12. ^ Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, et al. (July 2006). "Cutting edge: interleukin 17 signals through a heteromeric receptor complex". Journal of Immunology. 177 (1): 36–39. doi:10.4049/jimmunol.177.1.36. PMID 16785495. S2CID 45096063.
  13. ^ Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. (December 1995). "Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor". Immunity. 3 (6): 811–821. doi:10.1016/1074-7613(95)90070-5. PMID 8777726.
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