ArgBP2gamma interacts with Akt and p21-activated kinase-1 and promotes cell survival.
Akt/protein kinase B is a major cell survival pathway through phosphorylation of proapoptotic proteins Bad and Bax and of additional apoptotic pathways linked to Forkhead proteins glycogen synthase kinase-3beta and ASK1. To further explore the mechanism by which Akt regulates cell survival, we identified an Akt interaction protein by yeast two-hybrid screening. It is highly homologous to ARG-binding protein 2 (ArgBP2) with splicing exon 8 of the coding region of the ArgBP2. As two splicing isoforms (ArgBP2alpha and -beta) of ArgBP2 have been identified (Wang, B., Golemis, E. A., and Kruh, G. D. (1997) J. Biol. Chem. 272, 17542-17550), it was named ArgBP2gamma. ArgBP2gamma contains four Akt phosphorylation consensus sites, a SoHo motif, and three Src homology (SH) 3 domains and binds to C-terminal proline-rich motifs of Akt through its first and second SH3 domains. It also interacts with p21-activated protein kinase (PAK1) via its first and third SH3 domains, indicating the SH3 domains of ArgBP2gamma as docking sites for Akt and PAK1. Akt phosphorylates ArgBP2gamma in vitro and in vivo. Expression of ArgBP2gamma induces PAK1 activity and overrides apoptosis induced by ectopic expression of Bad or DNA damage. Nonphosphorylatable ArgBP2gamma-4A and SH3 domain-truncated mutant ArgBP2gamma inhibit Akt-induced PAK1 activation and reduce Akt and PAK1 phosphorylation of Bad and antiapoptotic function. These data indicate that ArgBP2gamma is a physiological substrate of Akt, functions as an adaptor for Akt and PAK1, and plays a role in Akt/PAK1 cell survival pathway.
Yuan
Zeng-qiang
ZQ
Department of Pathology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
Kim
Donghwa
D
Kaneko
Satoshi
S
Sussman
Melissa
M
Bokoch
Gary M
GM
Kruh
Gary D
GD
Nicosia
Santo V
SV
Testa
Joseph R
JR
Cheng
Jin Q
JQ
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005982:Glutathione Transferase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008954:Models, Biological; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016601:RNA-Binding Proteins; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D020798:Two-Hybrid System Techniques; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D054462:p21-Activated Kinases; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C494819:BAD protein, human; C494826:BAX protein, human; D002352:Carrier Proteins; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; C490755:SORBS2 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D011392:Proline; D005982:Glutathione Transferase; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue