CKLF like MARVEL transmembrane domain-containing 1

Last updated September 16, 2023

CKLF like MARVEL transmembrane domain-containing 1 (i.e. CMTM1), formerly termed chemokine-like factor superfamily 1 (i.e. CKLFSF1), has 23 known isoforms, the CMTM1-v1 to CMTM1-v23 proteins.^[1] Protein isoforms are variant products that are made by alternative splicing of a single gene. The gene for these isoforms, CMTM1 (formerly termed CKLFSF1), is located in band 22 on the long (i.e. "q") arm of chromosome 16.^[2] The CMTM1 gene and its 23 isoforms belong to the CKLF-like MARVEL transmembrane domain-containing family of structurally and functionally related genes and proteins.^[3] CMTM1 (isoforms not specified) proteins are weakly express in a wide range of normal tissues but are far more highly expressed in normal testes as well as the malignant cells of certain types of cancer.^[4]

Studies have reported that the levels of CMTM1 (typically the CMTM1–v17 isoform^[5]) are more highly expressed in breast, kidney, lung, ovary, liver (i.e. hepatocellular carcinoma), and salivary gland adenoid cystic carcinoma malignant tissues than the nearby normal tissues of these respective organs.^[5]^[4] According to the Human Protein Atlas, higher levels of CMTM1 expression in hepatocellular carcinoma tissues are associated with shorter survival times.^[4] Another study found that the levels of CMTM1 mRNA (which directs the production of CMTM1 protein) were higher in stomach cancer compared to nearby normal stomach tissues.^[5] And, studies of glioblastoma found no significant difference between the levels of CMTM1 in this brain tumor's tissues versus nearby normal brain tissues but higher levels of tumor tissue CMTM1 were associated with poorer prognoses.^[6] In addition, the forced overexpression of CMTM1 in cultured glioblastoma cell lines increased their proliferation and invasiveness.^[4] These findings suggest that CMTM1 proteins may act to promote the cited cancers and support further studies to determine if these proteins contribute to the development and/or progression of the cited cancers, can be used as markers of disease severity and/or prognosis, or are targets for treating these cancers.^[4]^[5]^[6]

In contrast to the findings in the cancers just cited, cell culture studies indicated that the forced overexpression of the CMTM1-v5 isoform induced apoptosis (i.e. cell death due to the activation of cell death-inducing signaling pathways) in two types of lymphoma cell lines, Jurkat cells (a human T cell leukemia cell line) and Raji cells (a human non-Hodgkin's lymphoma cell line). Simple addition of CMTM1-v5 protein to cultures of Daudi or Ramos cells (both are Burkitt's lymphoma cell lines) or Jurkat cells likewise caused these cells to become apoptotic. Various other cultured hematological tumor cell lines had no such response to the CMTM1-v5 protein. Finally, the injection of CMTM1-v5 into mice containing Raji cell tumors in a xenotransplantation model of cancer inhibited the spread of these tumors and prolonged the survival of the mice.^[7]^[8] These findings suggest that CMTM1-v5 protein may act to suppress certain types of lymphoma in humans and support initial studies to define the CMTM1-v5 levels in the malignant cells of humans with these lymphomas.^[7] Further studies are also needed to determine the basis for the CMTM1 proteins' promoting actions in the cited cancers versus suppressing actions in the cited lymphomas.^[8]

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CKLF-like MARVEL transmembrane domain-containing protein 2, previously termed chemokine-like factor superfamily 2, is a member of the CKLF-like MARVEL transmembrane domain-containing family (CMTM) of proteins. In humans, it is encoded by the CMTM2 gene located in band 22 on the long arm of chromosome 16. CMTM2 protein is expressed in the bone marrow and various circulating blood cells. It is also highly expressed in testicular tissues: The CMTM2 gene and CMTM2 protein, it is suggested, may play an important role in testicular development.

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CKLF like MARVEL transmembrane domain-containing 7, previously termed chemokine-like factor superfamily 7, is a protein that in humans is encoded by the CMTM7 gene. This gene, which is located in band 22 on the short arm of chromosome 3, and the protein that it encodes belong to the CKLF-like MARVEL transmembrane domain-containing family. Through the process of alternative splicing, the CMTM7 gene encodes two isoforms, CMTM7-v1 and CMTM7-v2, with CMTM7-v1 being the main form expressed and studied. CMTM7 proteins are widely expressed in normal human tissues.

Melanoma inhibitory activity protein 3 (MIA3), also known as transport and Golgi organization protein 1 (TANGO1), is a protein that in humans is encoded by the MIA3 gene on chromosome 1. It is ubiquitously expressed in many tissues and cell types. MIA3 localizes to the endoplasmic reticulum (ER) exit site, where it binds bulky cargo molecules such as collagens and creates mega transport carriers for the export of cargoes from the ER. This function suggests that it plays a role in assembly of extracellular matrix (ECM) and bone formation. MIA3 has been demonstrated to contribute to both tumor suppression and progression. The MIA3 gene also contains one of 27 loci associated with increased risk of coronary artery disease.. A TANGO1 like protein called TALI is expressed in liver and intestine and shown to be required for the export of bulky very Low density lipoproteins (VLDL) and chylomicrons. TANGO1 and TALI assemble into rings around COPII coats and this function is necessary for export of bulky cargoes. The discovery of TANGO1 and understanding its function has revealed that cargo export from the ER is not be vesicles but involves transient tunnels between the ER exit site and the next compartment of the secretory pathway. Biallelic Mutations in TANGO1 cause syndrome disease and complete loss of TANGO1 leads of defects in bone mineralization. These findings highlight the significance of TANGO1 in building and ER exit site, controlling the quantities and quality of cargo exported, which is necessary for life.

CKLF like MARVEL transmembrane domain-containing 6, previously termed chemokine-like factor superfamily 6, is a transmembrane protein encoded in humans by the CMTM6 gene. This gene is located in band 22.3 on the short arm of chromosome 3. CMTM6 protein belongs to the CKLF-like MARVEL transmembrane domain-containing family of proteins. This family consist of 9 member proteins: CKLF and CMTM1 through CMTM8. The CMTM family proteins are involved in autoimmune diseases, cardiovascular diseases, the male reproductive system, haematopoiesis, and cancer development. CMTM6 protein regulates immune responses to normal and abnormal cells.

CKLF-like MARVEL transmembrane domain-containing protein 3, also termed chemokine-like factor superfamily 3, is a member of the CKLF-like MARVEL transmembrane domain-containing family of proteins. In humans, CMTM2 protein is encoded by the CMTM3 gene located in band 22.1 on the long arm of chromosome 16. This protein is expressed in a wide range of tissues, including fetal tissues. It is highly expressed in the male reproductive system, particularly testicular tissues and may play a role in the development of this tissue. It is also highly expressed in the immune system including circulating blood cells, i.e. B lymphocytes, CD4+ T lymphocytes, and monocytes. However, CMTM3 protein is weakly expressed or unexpressed in the malignant tissues of several types of cancers. In many but not all of theses cancers, this decreased or lack of expression appears due to methylation of the GpC islands in the promoter region, and thereby the silencing, of the CMTM3 gene.

The CKLF-like MARVEL transmembrane domain-containing family (CMTM), previously termed the chemokine-like factor superfamily (CKLFSF), consists of 9 proteins, some of which have various isoforms due to alternative splicing of their respective genes. These proteins along with their isoforms are:

CKLF-like MARVEL transmembrane domain-containing 5 (CMTM5), previously termed chemokine-like factor superfamily 5, designates any one of the six protein isoforms encoded by six different alternative splices of its gene, CMTM5; CMTM5-v1 is the most studied of these isoforms. The CMTM5 gene is located in band 11.2 on the long arm of chromosome 14.

CKLF like MARVEL transmembrane domain-containing 8, previously termed chemokine-like factor superfamily 8 has at least two isoforms, the CMTM8 and CMTM8-v2 proteins. Protein isoforms are variant products that are made by the alternative splicing of a single gene. The gene for these isoforms, CMTM8, is located in band 22 on the short arm of chromosome 3. The CMTM8 gene and its CMTM8 and CMTM8-v2 proteins belong to the CKLF-like MARVEL transmembrane domain-containing family of structurally and functionally related genes and proteins. The CMTM8 protein is the full-length and predominant product of the CMTM8 gene. This protein is expressed in a wide range of normal adult and fetal tissues while relatively little is known about the CMTM8-v2 protein. Studies suggest that the CMTM8 protein may be involved in the development of various cancers.

CKLF like MARVEL transmembrane domain-containing 4, formerly termed chemokine-like factor superfamily 4, is a small transmembrane protein which passes the plasma membrane four times. It has 3 known isoforms, the CMTM4-v1 to CMTM4-v3 proteins. 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 arm of chromosome 16. 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. 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.

References

↑ Zhang W, Qi H, Mo X, Sun Q, Li T, Song Q, Xu K, Hu H, Ma D, Wang Y (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.
↑ 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.
↑ Han W, Ding P, Xu M, Wang L, Rui M, Shi S, Liu Y, Zheng Y, Chen Y, Yang T, Ma D (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): 609–17. doi:10.1016/s0888-7543(03)00095-8. PMID 12782130.
1 2 3 4 5 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.
1 2 3 4 Liang Z, Xie J, Huang L, Huang Y, Zhang Y, Ma R, Zheng Z, Wang Q, Li X (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.
1 2 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): 433–43. doi:10.1002/gcc.22255. PMID 25931111. S2CID 25545349.
1 2 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.
1 2 Cao L, Yang C, Zhu B, Zhang G, Zhao N, Liu X, Ke X, Chen W, Wang J, Wang L (December 2019). "A novel protein CMTM1-v5 specifically induced human lymphoma cells apoptosis in vitro and in vivo". Experimental Cell Research. 385 (1): 111623. doi:10.1016/j.yexcr.2019.111623. PMID 31542285. S2CID 202731429.

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[pmid26574634-1] Zhang W, Qi H, Mo X, Sun Q, Li T, Song Q, Xu K, Hu H, Ma D, Wang Y (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.

[pmid32195671-2] 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.

[pmid12782130-3] Han W, Ding P, Xu M, Wang L, Rui M, Shi S, Liu Y, Zheng Y, Chen Y, Yang T, Ma D (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): 609–17. doi:10.1016/s0888-7543(03)00095-8. PMID 12782130.

[pmid33282744-4] 1 2 3 4 5 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.

[pmid34012634-5] 1 2 3 4 Liang Z, Xie J, Huang L, Huang Y, Zhang Y, Ma R, Zheng Z, Wang Q, Li X (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.

[pmid25931111-6] 1 2 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): 433–43. doi:10.1002/gcc.22255. PMID 25931111. S2CID 25545349.

[pmid32944388-7] 1 2 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.

[pmid31542285-8] 1 2 Cao L, Yang C, Zhu B, Zhang G, Zhao N, Liu X, Ke X, Chen W, Wang J, Wang L (December 2019). "A novel protein CMTM1-v5 specifically induced human lymphoma cells apoptosis in vitro and in vivo". Experimental Cell Research. 385 (1): 111623. doi:10.1016/j.yexcr.2019.111623. PMID 31542285. S2CID 202731429.

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