Inhibition of Cdc42 is essential for Mig-6 suppression of cell migration induced by EGF
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Xinni Jiang1,*, MengMeng Niu1,*, Deshi Chen1, Jing Chen1, Yang Cao1, Xiaorong Li1,#, Haoqiang Ying2, Johann Bergholz1,3, Yujun Zhang1, Zhi-Xiong Xiao1
1Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610014, China
2Current address: The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3Current address: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
*These authors contributed equally to this work
Zhi-Xiong Xiao, email: [email protected]
Keywords: Mig-6, Cdc42, EGF, migration
Received: February 21, 2016 Accepted: May 12, 2016 Published: June 21, 2016
The adaptor protein Mig-6 is a negative regulator of EGF signaling. It is shown that Mig-6 inhibits cell migration via direct interaction with the ErbB receptors, thereby inhibiting cross-phosphorylation or targeting the receptors for degradation. Mig-6 has also been shown to bind to and inhibit the Rho GTPase Cdc42 to suppress cytoskeletal rearrangement. However, the molecular mechanism(s) by which Mig-6 inhibits cell migration via Cdc42 is still not entirely clear. Here, we show that Mig-6 binding to Cdc42 is necessary and sufficient to inhibit EGF-induced filopodia formation and migration. This binding, mediated by four specific residues (I11, R12, M26, R30) in the Mig-6 CRIB domain, is essential for Mig-6 function. In addition, ectopic expression of Cdc42 reverses Mig-6 inhibition of cell migration. Mig-6 CRIB domain, alone, is sufficient to inhibit cell migration. Conversely, Mig-6 binding to EGFR is dispensable for Mig-6-mediated inhibition of cell migration. Moreover, we found that decreased Mig-6 expression correlates with cancer progression in breast and prostate cancers. Together, our results demonstrate that Mig-6 inhibition of Cdc42 signaling is critical in Mig-6 function to suppress cell migration and that dysregulation of this pathway may play a critical role in cancer development.
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