title: Intramolecular interactions between the Dbl homology (DH) domain and the carboxyl-terminal region of myosin II-interacting guanine nucleotide exchange factor (MyoGEF) act as an autoinhibitory mechanism for the regulation of MyoGEF functions.
abstract: We have reported previously that nonmuscle myosin II-interacting guanine nucleotide exchange factor (MyoGEF) plays an important role in the regulation of cell migration and cytokinesis. Like many other guanine nucleotide exchange factors (GEFs), MyoGEF contains a Dbl homology (DH) domain and a pleckstrin homology domain. In this study, we provide evidence demonstrating that intramolecular interactions between the DH domain (residues 162-351) and the carboxyl-terminal region (501-790) of MyoGEF can inhibit MyoGEF functions. In vitro and in vivo pulldown assays showed that the carboxyl-terminal region (residues 501-790) of MyoGEF could interact with the DH domain but not with the pleckstrin homology domain. Expression of a MyoGEF carboxyl-terminal fragment (residues 501-790) decreased RhoA activation and suppressed actin filament formation in MDA-MB-231 breast cancer cells. Additionally, Matrigel invasion assays showed that exogenous expression of the MyoGEF carboxyl-terminal region decreased the invasion activity of MDA-MB-231 cells. Moreover, coimmunoprecipitation assays showed that phosphorylation of the MyoGEF carboxyl-terminal region by aurora B kinase interfered with the intramolecular interactions of MyoGEF. Furthermore, expression of the MyoGEF carboxyl-terminal region interfered with RhoA localization during cytokinesis and led to an increase in multinucleation. Together, our findings suggest that binding of the carboxyl-terminal region of MyoGEF to its DH domain acts as an autoinhibitory mechanism for the regulation of MyoGEF activation.
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458.
authors.forename: Meng
authors.initials: M
authors.lastname: Jiao
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458.
authors.forename: Shicheng
authors.initials: S
authors.lastname: Zu
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Sollecito
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458.
authors.forename: Kevin
authors.initials: K
authors.lastname: Jimenez-Cowell
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Mold
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Kennedy
authors.affiliation: From the Department of Biological Sciences, Fordham University, Bronx, New York 10458 qwei3@fordham.edu.
authors.forename: Qize
authors.initials: Q
authors.lastname: Wei
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry; D048749:Cytokinesis / Q000235:genetics*; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000737:chemistry; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011509:Proteoglycans / Q000737:chemistry; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D020662:Guanine Nucleotide Exchange Factors; D007797:Laminin; C527325:PLEKHG6 protein, human; D011509:Proteoglycans; C059485:matrigel; C066737:RHOA protein, human; D003094:Collagen; C576921:AURKB protein, human; D064107:Aurora Kinase B; D020742:rhoA GTP-Binding Protein
keywords: Cell Migration; Cytokinesis; Guanine Nucleotide Exchange Factor (GEF); MyoGEF; Myosin; Rho (Rho GTPase)