title: GRB2 couples RhoU to epidermal growth factor receptor signaling and cell migration.
abstract: RhoU is an atypical Rho family member with high homology to CDC42 but containing unique N- and C-terminal extensions. The mechanisms regulating RhoU activation, as well as its downstream effectors, are not fully characterized. We show that after epidermal growth factor (EGF) stimulation RhoU colocalizes with EGF receptor (EGFR) on endosomes, which requires both its N- and C-terminal extension sequences. Moreover, RhoU physically associates with activated EGFR in a GRB2-dependent manner through specific proline-rich motifs within its N-terminus. Mutation of these proline-rich sequences or suppression of GRB2 by RNA interference abrogates the interaction of RhoU with activated EGFR, as well as EGF-stimulated RhoU GTP binding. In addition, RhoU is involved in EGFR-mediated signaling, leading to AP1 transcriptional activity and cell migration in pancreatic cancer cells, events that require its interaction with the Grb2-EGFR complex. Taken together, the data suggest a unique regulatory mechanism by which RhoU interaction with SH3 adaptor proteins might serve to integrate growth factor receptor signaling with RhoU activation.
authors.affiliation: Division of Oncology Research and Schulze Center for Novel Therapeutics.
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.forename: Alexander
authors.initials: A
authors.lastname: Koenig
authors.forename: Charles
authors.initials: C
authors.lastname: Young
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D011992:Endosomes / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009154:Mutation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048670:MAP Kinase Kinase 4; C432668:RHOU protein, human; D020741:rho GTP-Binding Proteins