Citation Spotlight: Rac1 GTPase activity: Role in Lung Cancer Proliferation, Migration, and Metastasis

Recently, Jeganathan et al. examined the role of intersectin-1s (ITSN-1s) in lung cancer proliferation, migration, and metastasis. These cellular processes require actin cytoskeleton re-arrangement typically regulated by RhoA, Rac1, and/or Cdc42 GTPases. ITSN-1s is a multi-domain adaptor protein linking cell surface receptors to intracellular signaling cascades. ITSN-1s’s expression levels are reduced in human lung cancer cells and tissues. Among many findings, the authors report that ITSN-1s down-regulates the epidermal growth factor receptor kinase substrate 8 (Eps8) via ubiquitination and degradation, which in turn decreases the Eps8 and Ras/Rac1 guanine exchange factor mSos1 complex. The Eps8/mSos1 complex activates Rac1 which mediates the subsequent actin cytoskeletal re-arrangements necessary for cancer cell migration and metastasis. Restoration of normal ITSN-1s levels decreases Rac1 activation, increases RhoA activation (leaving Cdc42 activity unaffected), and results in a cytoskeletal network unfavorable to cancer cell migration and metastasis. Cytoskeleton’s RhoA, Rac1, and Cdc42 pull-down activation assays (Cat.# BK036, BK035, and BK034, respectively) were essential for the quantification of RhoA, Rac1, and Cdc42 activities across different levels of ITSN-1s expression. These results suggest that ITSN-1s could serve not only as a novel therapeutic target, but also a prognostic and therapeutic response indicator for lung cancer (and maybe others).

Jeganathan N. et al. 2016. Rac1-mediated cytoskeleton rearrangements induced by intersectin-1s deficiency promotes lung cancer cell proliferation, migration and metastasis. Mol. Cancer. 15, 59.