title: SmgGDS antagonizes BPGAP1-induced Ras/ERK activation and neuritogenesis in PC12 cell differentiation.
abstract: BPGAP1 is a Rho GTPase-activating protein (RhoGAP) that regulates cell morphogenesis, cell migration, and ERK signaling by the concerted action of its proline-rich region (PRR), RhoGAP domain, and the BNIP-2 and Cdc42GAP homology (BCH) domain. Although multiple cellular targets for the PRR and RhoGAP have been identified, and their functions delineated, the mechanism by which the BCH domain regulates functions of BPGAP1 remains unclear. Here we show that its BCH domain induced robust ERK activation leading to PC12 cell differentiation by targeting specifically to K-Ras. Such stimulatory effect was inhibited, however, by both dominant-negative mutants of Mek2 (Mek2-K101A) and K-Ras (K-Ras-S17N) and also by the small G-protein GDP dissociation stimulator (SmgGDS). Consequently SmgGDS knockdown released this inhibition and resulted in a superinduction of K-Ras activation and PC12 differentiation mediated by BCH domain. These results demonstrate the versatility of the BCH domain of BPGAP1 in regulating ERK signaling by involving K-Ras and SmgGDS and support the unique role of BPGAP1 as a dual regulator for Ras and Rho signaling in cell morphogenesis and differentiation.
authors.affiliation: Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Ravichandran
authors.forename: Boon Chuan
authors.initials: BC
authors.lastname: Low
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D016501:Neurites / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D059008:Time-Lapse Imaging
chemical_list: C581656:ARHGAP8 protein, rat; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C528430:Kras protein, rat; D034741:RNA, Small Interfering; C515969:smgGDS protein, rat; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)