Myosin-interacting guanine exchange factor (MyoGEF) regulates the  invasion activity of MDA-MB-231 breast cancer cells through activation  of RhoA and RhoC.
The small guanine triphosphatase (GTPase) proteins RhoA and RhoC are essential for tumor invasion and/or metastasis in breast carcinomas. However, it is poorly understood how RhoA and RhoC are activated in breast cancer cells. Here we describe the role of myosin-interacting guanine nucleotide exchange factor (Myo-GEF) in regulating RhoA and RhoC activation as well as cell polarity and invasion in an invasive breast cancer cell line MDA-MB-231. RNA-interference (RNAi)-mediated depletion of MyoGEF in MDA-MB-231 cells not only suppresses the activation of RhoA and RhoC, but also decreases cell polarity and invasion activity. The dominant-negative mutants of RhoA and RhoC, but not Rac1 and Cdc42, dramatically decrease actin polymerization induced by MyoGEF. In addition, MyoGEF co-localizes with nonmuscle myosin IIA (NMIIA) to the front of migrating cells, and depletion of NMIIA by RNAi disrupts the polarized localization of MyoGEF at the cell leading edge, suggesting a role for NMIIA in regulating MyoGEF localization and function. Moreover, MyoGEFprotein levels significantly increase in infiltrating ductal carcinomas as well as in invasive breast cancer cell lines. Taken together, our results suggest that MyoGEF cooperates with NMIIA to regulate the polarity and invasion activity of breast cancer cells through activation of RhoA and RhoC.
Department of Biochemistry, Kansas State University, Manhattan, KS 66506, USA.
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D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D044584:Carcinoma, Ductal / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005799:Genes, Dominant / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009218:Myosins / Q000378:metabolism*; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D034622:RNA Interference; D013379:Substrate Specificity; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D024507:Nonmuscle Myosin Type IIA; D009218:Myosins; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein