Sos-mediated activation of rac1 by p66shc.
The Son of Sevenless 1 protein (sos1) is a guanine nucleotide exchange factor (GEF) for either the ras or rac1 GTPase. We show that p66shc, an adaptor protein that promotes oxidative stress, increases the rac1-specific GEF activity of sos1, resulting in rac1 activation. P66shc decreases sos1 bound to the growth factor receptor bound protein (grb2) and increases the formation of the sos1-eps8-e3b1 tricomplex. The NH(2)-terminal proline-rich collagen homology 2 (CH2) domain of p66shc associates with full-length grb2 in vitro via the COOH-terminal src homology 3 (C-SH3) domain of grb2. A proline-rich motif (PPLP) in the CH2 domain mediates this association. The CH2 domain competes with the proline-rich COOH-terminal region of sos1 for the C-SH3 domain of grb2. P66shc-induced dissociation of sos1 from grb2, formation of the sos1-eps8-e3b1 complex, rac1-specific GEF activity of sos1, rac1 activation, and oxidative stress are also mediated by the PPLP motif in the CH2 domain. This relationship between p66shc, grb2, and sos1 provides a novel mechanism for the activation of rac1.
Khanday
Firdous A
FA
Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Santhanam
Lakshmi
L
Kasuno
Kenji
K
Yamamori
Tohru
T
Naqvi
Asma
A
Dericco
Jeremy
J
Bugayenko
Artem
A
Mattagajasingh
Ilwola
I
Disanza
Andrea
A
Scita
Giorgio
G
Irani
Kaikobad
K
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005347:Fibroblasts; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D017434:Protein Structure, Tertiary / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D020664:Son of Sevenless Proteins / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C513734:Abi1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D046911:Macromolecular Substances; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D020664:Son of Sevenless Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020830:rac1 GTP-Binding Protein