Research Abstract

My laboratory focuses on novel molecules and pathways that control tumor growth, metastasis and drug resistance. We study a tetraspanin protein, called CD151, that associates with laminin-binding integrins and regulates their contributions to tumor initiation, promotion, progression, invasion and metastasis. Also we have gained new molecular insights into how a novel subpopulation of CD151 supports resistance to many anti-cancer drugs. Also, we have uncovered novel positive and negative regulators of TGF-β signaling. We learned that tetraspanin proteins CD9 and CD81 make vital contributions towards TGF-β1 receptor assembly and signaling. Conversely, the EWI-2 protein associates tightly with CD9 and CD81, thus inhibiting TGF-β1 signaling. These findings have wide implications and provide novel insights into dual roles of TGF-β1 as it inhibits primary tumor growth, but supports EMT, invasion and metastasis. Additionally, we noted that assembly of protein complexes, called tetraspanin-enriched microdomains (TEMS) is facilitated by palmitoylation of tetraspanins, integrins, and other proteins found within TEMS. We learned that palmitoylation of tetraspanin proteins is largely mediated by a palmitoyl acyl transferase called DHHC2, whereas palmitoylation of integrin α6 and β4 subunits is mediated by DHHC3. In further studies of DHHC3, we found that it is a major contributor to tumor growth in vivo, by a mechanism that involves negative regulation of oxidative stress and senescence in tumor cells.