CKLF like MARVEL transmembrane domain-containing 4 explained

CKLF-like MARVEL transmembrane domain-containing protein 4
Altnames:Chemokine-like factor superfamily member 4
Symbol:CMTM4
Altsymbols:CKLFSF4
Hgncid:19175
Omim:607887
Refseq:NM_178818.3
Uniprot:Q8IZR5
Chromosome:16
Arm:q
Band:21-q22.1

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,[8] neuroblastomas, and medulloblastomas, compared to their levels in nearby normal, non-tumorous brain tissues.[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.[10]

CMTM4 in IL-17A signaling

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.

Notes and References

  1. Zhang W, Qi H, Mo X, Sun Q, Li T, Song Q, Xu K, Hu H, Ma D, Wang Y . 6 . CMTM8 is Frequently Downregulated in Multiple Solid Tumors . Applied Immunohistochemistry & Molecular Morphology . 25 . 2 . 122–128 . February 2017 . 26574634 . 10.1097/PAI.0000000000000274 . 205912507 .
  2. Duan HJ, Li XY, Liu C, Deng XL . Chemokine-like factor-like MARVEL transmembrane domain-containing family in autoimmune diseases . Chinese Medical Journal . 133 . 8 . 951–958 . April 2020 . 32195671 . 7176445 . 10.1097/CM9.0000000000000747 .
  3. Han W, Ding P, Xu M, Wang L, Rui M, Shi S, Liu Y, Zheng Y, Chen Y, Yang T, Ma D . 6 . 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 . June 2003 . 12782130 . 10.1016/s0888-7543(03)00095-8 .
  4. Li M, Luo F, Tian X, Yin S, Zhou L, Zheng S . Chemokine-Like Factor-Like MARVEL Transmembrane Domain-Containing Family in Hepatocellular Carcinoma: Latest Advances . Frontiers in Oncology . 10 . 595973 . 2020 . 33282744 . 7691587 . 10.3389/fonc.2020.595973 . free .
  5. Ge YY, Duan HJ, Deng XL . Possible effects of chemokine-like factor-like MARVEL transmembrane domain-containing family on antiphospholipid syndrome . Chinese Medical Journal . 134 . 14 . 1661–1668 . April 2021 . 33813507 . 8318642 . 10.1097/CM9.0000000000001449 .
  6. Xue H, Li T, Wang P, Mo X, Zhang H, Ding S, Ma D, Lv W, Zhang J, Han W . 6 . 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 . September 2019 . 31435638 . 10.1093/abbs/gmz084 .
  7. Li T, Cheng Y, Wang P, Wang W, Hu F, Mo X, Lv H, Xu T, Han W . 6 . CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma . Journal of Experimental & Clinical Cancer Research . 34 . 122 . October 2015 . 26474560 . 4609138 . 10.1186/s13046-015-0236-4 . free .
  8. Delic S, Thuy A, Schulze M, Proescholdt MA, Dietrich P, Bosserhoff AK, Riemenschneider MJ . 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 . July 2015 . 25931111 . 10.1002/gcc.22255 . 25545349 .
  9. Wu J, Li L, Wu S, Xu B . CMTM family proteins 1-8: roles in cancer biological processes and potential clinical value . Cancer Biology & Medicine . 17 . 3 . 528–542 . August 2020 . 32944388 . 7476098 . 10.20892/j.issn.2095-3941.2020.0032 .
  10. Liang Z, Xie J, Huang L, Huang Y, Zhang Y, Ma R, Zheng Z, Wang Q, Li X . 6 . 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 . April 2021 . 34012634 . 8107618 . 10.21037/jgo-21-78 . free .
  11. Knizkova D, Pribikova M, Draberova H, Semberova T, Trivic T, Synackova A, Ujevic A, Stefanovic J, Drobek A, Huranova M, Niederlova V, Tsyklauri O, Neuwirth A, Tureckova J, Stepanek O, Draber P . 6 . CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology . Nature Immunology . 23 . 11 . 1644–1652 . November 2022 . 36271145 . 9663306 . 10.1038/s41590-022-01325-9 .
  12. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J . 6 . Cutting edge: interleukin 17 signals through a heteromeric receptor complex . Journal of Immunology . 177 . 1 . 36–39 . July 2006 . 16785495 . 10.4049/jimmunol.177.1.36 . 45096063 . free .
  13. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, Cohen JI, Spriggs MK . 6 . Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor . Immunity . 3 . 6 . 811–821 . December 1995 . 8777726 . 10.1016/1074-7613(95)90070-5 . free .

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