Review of the GAS3 Family of Proteins and their Relevance to Cancer

Abstract

The GAS3 family of tetraspan proteins has recently been implicated in the progression of cancer. Currently, six members of the GAS3 family have been identified in humans and mice, and while their expressions in disease vary, data suggest that they play a role in epithelial cell structure and function. In this review, we highlight the studies implicating four of the members in disease pathogenesis as well as probe the structural similarities between the family members. Finally, the impact of targeting select members of the family such as PMP22 and EMP2 is discussed.

Elevated Peripheral Myelin Protein 22, Reduced Mitotic Potential, and Proteasome Impairment in Dermal Fibroblasts from Charcot-Marie-Tooth Disease Type 1A Patients

“…In general, however, PMP22 message levels appear to vary in human biopsy material, which led to the suggestion that the extra copy of the PMP22 gene disrupts gene regulatory mechanisms 42 . Furthermore, there are numerous reports on aberrant PMP22 expression in cancer biopsies, including osteosarcoma and breast cancer, 43 with the levels of PMP22 expression not necessarily correlating with the mitotic state of the cells. Therefore, more studies with larger sample numbers are necessary before the precise utility of CMT1A patient–derived cells for therapy development and testing can be unequivocally established.…”

Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype

“…Proposed posttranslational modification sites are indicated. Model similar to previously published EMP family model 35 . b Predicted effects of first extracellular loop interactions with the membrane interface and consequence for apparent membrane thickness.…”

Genetic Deletion of Emp2 Does Not Cause Proteinuric Kidney Disease in Mice

“…EMP2 is a member of the growth arrest-specific gene 3/peripheral myelin protein 22 (GAS3/PMP22) family of tetraspan proteins (10–12). Mapped to chromosome 16p13.2, EMP2 was initially identified by its close homology with PMP22 (~40% amino acid sequence similarity) (13, 14). EMP2 translates to an 18 kD protein with four transmembrane domains and multiple consensus sites for N-linked glycosylation in the first hydrophilic domain (13, 15).…”

“…EMP2 translates to an 18 kD protein with four transmembrane domains and multiple consensus sites for N-linked glycosylation in the first hydrophilic domain (13, 15). Tissue distribution and cellular localization of EMP2 has not been fully characterized before although EMP2 is known to be prominently expressed in the lungs (10, 14, 16–18). Several cellular functions have been ascribed to EMP2 including: (1) regulation of cell adhesion involving FAK/Src and β1-integrin; (2) facilitation of trafficking of glycophosphatidylinositol (GPI)-anchored proteins into lipid rafts and regulation of caveolar organization; and, (4) regulation of angiogenesis through induction of VEGFA expression (10, 12, 17, 19–21).…”

“…Several cellular functions have been ascribed to EMP2 including: (1) regulation of cell adhesion involving FAK/Src and β1-integrin; (2) facilitation of trafficking of glycophosphatidylinositol (GPI)-anchored proteins into lipid rafts and regulation of caveolar organization; and, (4) regulation of angiogenesis through induction of VEGFA expression (10, 12, 17, 19–21). EMP2 expression is upregulated in a number of human cancers including endometrial cancers, ovarian cancers, glioblastomas, urinary bladder urothelial carcinoma, and nasopharyngeal carcinomas (10, 14, 22) where it likely plays a role in tumorigenesis through modulation of integrin-dependent cell adhesion (23, 24) and/or promotion of neoplastic angiogenesis (21, 23). EMP2 has been shown to be important for blastocyst implantation and has been identified as a susceptibility factor for chlamydial infectivity, both likely via its role in regulation of integrin-dependent cell signaling (25–27).…”