p21-activated kinase 1 (PAK1) interacts with the Grb2 adapter protein to couple to growth factor signaling.
A variety of intracellular signaling pathways are linked to cell surface receptor signaling through their recruitment by Src homology 2 (SH2)/SH3-containing adapter molecules. p21-activated kinase 1 (PAK1) is an effector of Rac/Cdc42 GTPases that has been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. In this study, we describe the specific interaction of PAK1 with the Grb2 adapter protein both in vitro and in vivo. We identify the site of this interaction as the second proline-rich SH3 binding domain of PAK1. Stimulation of the epidermal growth factor receptor (EGFR) in HaCaT cells enhances the level of EGFR-associated PAK1 and Grb2, although the PAK1-Grb2 association is itself independent of this stimulation. A cell-permeant TAT-tagged peptide encompassing the second proline-rich SH3 binding domain of PAK1 simultaneously blocked Grb2 and activated EGFR association with PAK1, in vitro and in vivo, indicating that Grb2 mediates the interaction of PAK1 with the activated EGFR. Blockade of this interaction decreased the epidermal growth factor-induced extension of membrane lamellae. Thus Grb2 may serve as an important mechanism for linking downstream PAK signaling to various upstream pathways.
Puto
Lorena A
LA
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Pestonjamasp
Kersi
K
King
Charles C
CC
Bokoch
Gary M
GM
D048868:Adaptor Proteins, Signal Transducing; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D054462:p21-Activated Kinases; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D006133:Growth Substances; D010455:Peptides; D011506:Proteins; D014443:Tyrosine; D066246:ErbB Receptors; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases