Alternative titles; symbols
HGNC Approved Gene Symbol: TM4SF1
Cytogenetic location: 3q25.1 Genomic coordinates (GRCh38): 3:149,369,022-149,377,649 (from NCBI)
TM4SF1 functions in growth, motility, invasion, and metastasis of tumor cells. It regulates angiogenesis by endothelial cells (summary by Shih et al., 2009).
The L6 cell surface antigen, which is highly expressed in lung, breast, colon, and ovarian carcinomas, attracted attention as a therapeutic target for monoclonal antibodies. Marken et al. (1992) cloned a cDNA encoding the L6 antigen. The predicted 202-amino acid peptide contains 3 predicted N-terminal hydrophobic transmembrane regions, followed by a hydrophilic region with 2 potential N-linked glycosylation sites and a C-terminal hydrophobic transmembrane region.
Shih et al. (2009) found that TM4SF1 mRNA was highly expressed in human endothelial cells cultured from several tissues. It showed much weaker expression in human dermal fibroblasts and smooth muscle cells. Immunofluorescence microscopy localized TM4SF1 to endothelial cell filopodia, where it showed an intermittent, banded pattern of expression.
Shih et al. (2009) found that short hairpin RNA-mediated knockdown of TM4SF1 in human umbilical vein endothelial cells (HUVECs) resulted in the accumulation of numerous circumferential stress fibers, incomplete cytokinesis, arrest in G2-M, and the appearance of binucleated or multinucleated cells. HUVECs survived TM4SF1 knockdown, but they lost the ability to migrate, form tubes in 3-dimensional cultures, and proliferate in response to VEGFA (192240). Immunoprecipitation analysis revealed that TM4SF1 interacted constitutively with the integrins alpha-5 (ITGA5; 135620) and beta-1 (ITGB1; 135630), and stimulation of HUVECs with VEGFA or thrombin (F2; 176930) induced TM4SF1 to interact with integrin alpha-V (ITGAV; 193210) and its partners beta-3 (ITGB3; 173470) and beta-5 (ITGB5; 147561). Tm4sf1 knockdown inhibited vascular maturation stimulated by VEGFA in a mouse ear angiogenesis model. Shih et al. (2009) concluded that TM4SF1 is a key regulator of angiogenesis.
Virtaneva et al. (1994) mapped the TM4SF1 gene to chromosome 3q21-q25 by hybridization to a panel of chromosome 3 derivative somatic cell hybrid DNAs.
Marken, J. S., Schieven, G. L., Hellstrom, I., Hellstrom, K. E., Aruffo, A. Cloning and expression of the tumor-associated antigen L6. Proc. Nat. Acad. Sci. 89: 3503-3507, 1992. [PubMed: 1565644] [Full Text: https://doi.org/10.1073/pnas.89.8.3503]
Shih, S.-C., Zukauskas, A., Li, D., Liu, G., Ang, L.-H., Nagy, J. A., Brown, L. F., Dvorak, H. F. The L6 protein TM4SF1 is critical for endothelial cell function and tumor angiogenesis. Cancer Res. 69: 3272-3277, 2009. [PubMed: 19351819] [Full Text: https://doi.org/10.1158/0008-5472.CAN-08-4886]
Virtaneva, K. I., Emi, N., Marken, J. S., Aruffo, A., Jones, C., Spurr, N. K., Schroder, J. P. Chromosomal localization of three human genes coding for A15, L6, and S5.7 (TAPA1): all members of the transmembrane 4 superfamily of proteins. Immunogenetics 39: 329-334, 1994. [PubMed: 8168850] [Full Text: https://doi.org/10.1007/BF00189229]