Epithelial Membrane Protein-2 (EMP2) Activates Src Protein and Is a Novel Therapeutic Target for Glioblastoma

Yu, Qin; M, Fu; Takahashi, Manabu; Iwanami, Akio; Kuga, Daisuke; Rao, Rajiv G; Sudhakar, Deepthi; Huang, Tiffany; Kiyohara, Meagan; Torres, Kathleen; Dillard, Christen; Inagaki, Akihito; Kasahara, Noriyuki; Goodglick, Lee; Braun, Jonathan; Mischel, Paul S.; Gordon, Lynn K.; Wadehra, Madhuri

doi:10.1074/jbc.m113.543728

Cited by 40 publications

(56 citation statements)

References 50 publications

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“…Being a member of the tetraspan protein superfamily, EMP2 is known to interact with and regulate a number of important cell adhesion and cell signaling molecules, such as b1 integrin, 4 FAK, and Src, 31,32 which are also known to play important roles in podocytes. The mechanisms by which expression and activity of these proteins are affected by EMP2 deletion and how it subsequently influences podocyte function and health deserve further investigation.…”

Section: Discussionmentioning

confidence: 99%

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Wan

Chen

Choi

et al. 2016

Journal of the American Society of Nephrology

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Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease-based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury. Nephrotic syndrome (NS) is a CKD defined by nephrotic-range proteinuria caused by disruption of the renal glomerular filtration barrier, resulting in hypoalbuminemia, hyperlipidemia, and edema. Childhood NS, if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. 1 NS is classified by response or nonresponse to a standardized glucocorticosteroid therapy as steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS), respectively. Recent studies of SRNS have identified monogenic causes of SRNS to reside in podocytespecific genes, which if mutated, lead to podocyte dysfunction and defective glomerular filtration barrier. 2 Using the combined approach of homozygosity mapping and whole-exome sequencing, we have previously identified mutations in epithelial membrane protein 2 (EMP2) as a novel monogenic cause for NS. 3 EMP2 was initially identified by its homology with the growth-arrest-specific 3/peripheral myelin protein 22 family 4 and negatively regulates the mRNA and protein levels of CAV1, a major protein component of plasma membrane microdomain caveolae. 5,6 To explore the pathogenic mechanism underlying EMP2 mutations, we have now generated emp2

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Section: Discussionmentioning

confidence: 99%

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Wan

Chen

Choi

et al. 2016

Journal of the American Society of Nephrology

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“…Anti-EMP2 antibody therapy successfully decreased tumor load in subcutaneous mouse models and enhanced GBM cell death in vitro . 90 These results suggest anti-EMP2 therapy may be of value in the pathogenesis of GBM.…”

Section: Emps (Emp1 Emp2 and Emp3)mentioning

confidence: 92%

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

Ashki¹,

Gordon

Wadehra

2015

Crit Rev Oncog

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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.

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“…This has been shown in both epithelial tumors of the uterus and breast, as well as in primary CNS malignancies. 11,52,53 As such, targeting EMP2 would be predicted to reduce FAK activation. Our laboratory has been instrumental in creating a panel of antibodies and antibody fragments to target EMP2, and we have shown that these reagents specifically localize to EMP2 positive tumors with minimal targeting to normal tissue, suggesting that EMP2 is normally sequestered.…”

Section: Fak Inhibitorsmentioning

confidence: 99%

Regulation of FAK Activity by Tetraspan Proteins: Potential Clinical Implications in Cancer

Mohandessi

Gordon

et al. 2015

Crit Rev Oncog

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that regulates multiple cell signaling pathways in both physiological and pathological conditions. Overexpression and activation of FAK is associated with many advanced stage cancers through promoting cancer cell tumorigenicity and progression as well as by regulating the tumor microenvironment. FAK has multiple binding partners through which FAK exerts its functions including RhoGEF, Src family, talin, cortactin, and paxilin. Over the last few years, it has been proposed that a novel group of four transmembrane proteins can interact with FAK and regulate its activity. These include select tetraspanins such as CD151 and CD9 as well as the GAS3 family members epithelial membrane protein-2 (EMP2) and peripheral myelin protein-22 (PMP22). In this review, we discuss the current knowledge of the interaction between FAK and tetraspan proteins in physiological and pathological conditions, with an emphasis on the potential of tetraspan family members as therapeutic targets in cancer.

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Epithelial Membrane Protein-2 (EMP2) Activates Src Protein and Is a Novel Therapeutic Target for Glioblastoma

Cited by 40 publications

References 50 publications

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

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

Regulation of FAK Activity by Tetraspan Proteins: Potential Clinical Implications in Cancer

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