title: One-way membrane trafficking of SOS in receptor-triggered Ras activation.
abstract: SOS is a key activator of the small GTPase Ras. In cells, SOS-Ras signaling is thought to be initiated predominantly by membrane recruitment of SOS via the adaptor Grb2 and balanced by rapidly reversible Grb2-SOS binding kinetics. However, SOS has multiple protein and lipid interactions that provide linkage to the membrane. In reconstituted-membrane experiments, these Grb2-independent interactions were sufficient to retain human SOS on the membrane for many minutes, during which a single SOS molecule could processively activate thousands of Ras molecules. These observations raised questions concerning how receptors maintain control of SOS in cells and how membrane-recruited SOS is ultimately released. We addressed these questions in quantitative assays of reconstituted SOS-deficient chicken B-cell signaling systems combined with single-molecule measurements in supported membranes. These studies revealed an essentially one-way trafficking process in which membrane-recruited SOS remains trapped on the membrane and continuously activates Ras until being actively removed via endocytosis.
authors: Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
authors: Sune M
authors: SM
authors: Christensen
authors: Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
authors: Hsiung-Lin
authors: HL
authors: Tu
authors: Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.
authors: Jesse E
authors: JE
authors: Jun
authors: Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
authors: Steven
authors: S
authors: Alvarez
authors: Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
authors: Meredith G
authors: MG
authors: Triplet
authors: Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
authors: Jeffrey S
authors: JS
authors: Iwig
authors: Department of Biochemistry, New York University School of Medicine, New York, New York, USA.
authors: Kamlesh K
authors: KK
authors: Yadav
authors: Department of Biochemistry, New York University School of Medicine, New York, New York, USA.
authors: Dafna
authors: D
authors: Bar-Sagi
authors: Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.
authors: Jeroen P
authors: JP
authors: Roose
authors: Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
authors: Jay T
authors: JT
authors: Groves
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002645:Chickens; D004705:Endocytosis; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry; D020935:MAP Kinase Signaling System; D011485:Protein Binding; D000072417:Protein Domains; D021381:Protein Transport; D051562:Proto-Oncogene Proteins c-bcr / Q000502:physiology; D020837:SOS1 Protein / Q000737:chemistry / Q000502:physiology*; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D020837:SOS1 Protein; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D018631:ras Proteins