title: Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling.
abstract: Human Sin1 (SAPK-interacting protein 1) is a member of a conserved family of orthologous proteins that have an essential role in signal transduction in yeast and Dictyostelium. This study demonstrates that most Sin1 orthologues contain both a Raf-like Ras-binding domain (RBD) and a pleckstrin homology (PH) domain. These domains are functional in the human Sin1 protein, with the PH domain involved in lipid and membrane binding by Sin1, and the RBD able to bind activated H-and K-Ras. Sin1 and Ras co-immunoprecipitated and co-localised, showing that these proteins associate with each other in vivo. Overexpression of Sin1 inhibited the activation of ERK, Akt and JNK signalling pathways by Ras. In contrast, siRNA knockdown of endogenous Sin1 protein expression in HEK293 cells enhanced the activation of ERK1/2 by Ras. These data suggest that Sin1 is a mammalian Ras-inhibitor.
authors.affiliation: The Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Schroder
authors.forename: Marion
authors.initials: M
authors.lastname: Buck
authors.forename: Nicole
authors.initials: N
authors.lastname: Cloonan
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
authors.forename: Andreas
authors.initials: A
authors.lastname: Suhrbier
authors.forename: Tom
authors.initials: T
authors.lastname: Sculley
authors.forename: Gillian
authors.initials: G
authors.lastname: Bushell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004789:Enzyme Activation; D006801:Humans; D008055:Lipids; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008055:Lipids; C493277:MAPKAP1 protein, human; D018631:ras Proteins