title: Inhibition of Cdc42 is essential for Mig-6 suppression of cell migration induced by EGF.
abstract: 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.
authors.affiliation: Center 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.
authors.forename: Xinni
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Center 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.
authors.forename: MengMeng
authors.initials: M
authors.lastname: Niu
authors.affiliation: Center 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.
authors.forename: Deshi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Center 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Center 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Center 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.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Li
authors.affiliation: Current address: The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.affiliation: Center 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.|Current address: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Johann
authors.initials: J
authors.lastname: Bergholz
authors.affiliation: Center 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.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center 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.
authors.forename: Zhi-Xiong
authors.initials: ZX
authors.lastname: Xiao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000596:Amino Acids / Q000737:chemistry; D001943:Breast Neoplasms / Q000378:metabolism; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; C484017:ERRFI1 protein, human; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D020764:cdc42 GTP-Binding Protein
keywords: Cdc42; EGF; Mig-6; migration