title: CIIA negatively regulates the Ras-Erk1/2 signaling pathway through inhibiting the Ras-specific GEF activity of SOS1.
abstract: Son of sevenless 1 (SOS1) is a Ras-specific guanine-nucleotide-exchange factor (GEF) that mediates intracellular signaling processes induced by receptor tyrosine kinases. In this study, we show that CIIA (also known as VPS28) physically associates with SOS1 and thereby inhibits the GEF activity of SOS1 on Ras, which prevents the epidermal growth factor (EGF)-induced activation of the Ras-Erk1/2 pathway. Furthermore, CIIA inhibited cyclin D1 expression, as well as DNA, synthesis in response to EGF. Intriguingly, CIIA failed to inhibit the Ras-specific GEF activity of Noonan-syndrome-associated SOS1 mutants (M269R, R552G, W729L and E846K). Taken together, our results suggest that CIIA functions as a negative modulator of the SOS1-Ras signaling events initiated by peptide growth factors including EGF.
authors: Laboratory of Cell Death and Human Diseases, Department of Life Sciences, Korea University, Seoul 136-701, South Korea.
authors: Hyun Sub
authors: HS
authors: Hwang
authors: Sang Gil
authors: SG
authors: Hwang
authors: Kyoung-Wan
authors: KW
authors: Yoon
authors: Je-Hyun
authors: JH
authors: Yoon
authors: Kyung-Hye
authors: KH
authors: Roh
authors: Eui-Ju
authors: EJ
authors: Choi
mesh_terms: D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004285:Dogs; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009634:Noonan Syndrome / Q000235:genetics; D020837:SOS1 Protein / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D020662:Guanine Nucleotide Exchange Factors; D020837:SOS1 Protein; C476409:VPS28 protein, human; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins
keywords: CIIA; Ras; SOS1; VPS28