ADAM15

Function

The protein encoded by this gene is a member of the ADAM (a disintegrin and metalloproteinase) protein family. ADAM family members are type I transmembrane glycoproteins known to be involved in cell adhesion and proteolytic ectodomain processing of cytokines and adhesion molecules. This protein contains multiple functional domains including a zinc-binding metalloprotease domain, a disintegrin-like domain, as well as an EGF-like domain. Through its disintegrin-like domain, this protein specifically interacts with the integrin beta chain, beta 3. It also interacts with Src family protein-tyrosine kinases in a phosphorylation-dependent manner, suggesting that this protein may function in cell-cell adhesion as well as in cellular signaling. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed.

Clinical significance

Arthritis

ADAM15 has been associated with a number of diseases, most recently Rheumatoid Arthritis where it is required for the activation of the FAK and Src pathways to generate apoptosis resistance in response to apoptotic signalling or cell stress. ADAM15 also has an antiapoptotic effect in osteoarthritic chondrocytes.

Cancer

The precise role of ADAM15 in cancer is still unclear but the metalloprotein has been linked to a number of different cancerous diseases such as Breast cancer where the expression of the protein is increased in carcinoma in-situ, invasive carcinoma and metastatic breast cancer tissues Additionally, the alternative splice variant forms of ADAM15 have also been correlated with different prognosis in 48 breast cancer patients based upon their expression levels.

Interactions

ADAM15 has been shown to interact with:

• Grb2,
• HCK,
• Lck and
• SH3GL2, and
• SNX9.

The alternatively spliced isoforms have also been shown to exhibit different preferential interactions with proteins containing SH3 domains.

References

References

1. (April 1998). "Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3". J Biol Chem.
2. "Entrez Gene: ADAM15 ADAM metallopeptidase domain 15 (metargidin)".
3. (November 2013). "ADAM15 adds to apoptosis resistance of synovial fibroblasts by modulating focal adhesion kinase signaling". Arthritis Rheum..
4. (May 2010). "ADAM15 exerts an antiapoptotic effect on osteoarthritic chondrocytes via up-regulation of the X-linked inhibitor of apoptosis". Arthritis Rheum..
5. (April 2006). "ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease". Neoplasia.
6. (February 2008). "ADAM15 supports prostate cancer metastasis by modulating tumor cell-endothelial cell interaction". Cancer Res..
7. (February 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". J. Biol. Chem..
8. (October 1999). "Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1". J. Biol. Chem..
9. (March 2008). "Distinct functions of natural ADAM-15 cytoplasmic domain variants in human mammary carcinoma". Mol. Cancer Res..
10. (November 2009). "Alternative splicing of ADAM15 regulates its interactions with cellular SH3 proteins". J. Cell. Biochem..