Regulation of the Cool/Pix proteins - Key binding partners of the Cdc42/Rac targets, the p21-activated kinases

被引:88
作者
Feng, QY
Albeck, JG
Cerione, RA
Yang, WN [1 ]
机构
[1] Cornell Univ, Dept Mol Med, Ithaca, NY 14853 USA
[2] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA
关键词
D O I
10.1074/jbc.M107704200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Cool (cloned-out of library)/Pix (for PAR-interactive exchange factor) proteins directly bind to members of the PAK family of serine/threonine kinases and regulate their activity. Three members of the Cool/Pix family have shown distinct regulatory activities: (D p50(Cool-1) inhibits Cdc42/Rac-stimulated PAK activity, (ii) p85(Cool-1)/beta-Pix has a permissive effect on Cdc42/Rac-stimulated activity, and (iii) p90(Cool-2)/alpha-Pix strongly activates PAR. We initially suspected that these different functional effects were due to a binding interaction that occurs at the carboxyl-terminal ends of the larger Cool/Pix proteins, thus enabling them to stimulate (or at least permit) rather than inhibit PAK activity. This led to the identification of the Cat proteins (for Cool-associated tyrosine phosphosubstrates). However, here we show that the Cat proteins bind to the carboxyl-terminal ends of p85(Cool-1) (residues 523-546) and Cool-2 (residues 647-670), and that the binding of Cat to Cool-2 in fact is not necessary for the Cool-2-mediated activation of PAY, Rather, an 18-amino acid region, designated T1, that is present in the Cool-1 proteins, but missing in Cool-2, is essential for controlling the regulation of PAK activity by Cool-l/beta-Pix in vivo. Deletion of T1 yielded a p85(Cool-1) molecule that mimicked the Cool-2 protein and was capable of strongly stimulating PAR activity. However, when T1 was added to Cool-2, the ability of Cool-2 to directly activate PAK was lost. We conclude that T1 represents a novel regulatory domain that accounts for the specific functional effects on PAK activity exhibited by the different members of the Cool/Pix family.
引用
收藏
页码:5644 / 5650
页数:7
相关论文
共 38 条
[1]   Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase [J].
Adam, L ;
Vadlamudi, R ;
Kondapaka, SB ;
Chernoff, J ;
Mendelsohn, J ;
Kumar, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (43) :28238-28246
[2]   Two GTPases, cdc42 and rac, bind directly to a protein implicated in the immunodeficiency disorder Wiskott-Aldrich syndrome [J].
Aspenstrom, P ;
Lindberg, U ;
Hall, A .
CURRENT BIOLOGY, 1996, 6 (01) :70-75
[3]   IDENTIFICATION OF A MOUSE P21(CDC42/RAC) ACTIVATED KINASE [J].
BAGRODIA, S ;
TAYLOR, SJ ;
CREASY, CL ;
CHERNOFF, J ;
CERIONE, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (39) :22731-22737
[4]   PAK to the future [J].
Bagrodia, S ;
Cerione, RA .
TRENDS IN CELL BIOLOGY, 1999, 9 (09) :350-355
[5]   A novel regulator of p21-activated kinases [J].
Bagrodia, S ;
Taylor, SJ ;
Jordon, KA ;
Van Aelst, L ;
Cerione, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (37) :23633-23636
[6]  
BAGRODIA S, 1995, J BIOL CHEM, V270, P27995
[7]   A tyrosine-phosphorylated protein that binds to an important regulatory region on the cool family of p21-activated kinase-binding proteins [J].
Bagrodia, S ;
Bailey, D ;
Lenard, Z ;
Hart, M ;
Guan, JL ;
Premont, RT ;
Taylor, SJ ;
Cerione, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (32) :22393-22400
[8]   Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway [J].
Brown, JL ;
Stowers, L ;
Baer, M ;
Trejo, J ;
Coughlin, S ;
Chant, J .
CURRENT BIOLOGY, 1996, 6 (05) :598-605
[9]   The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1 [J].
Chou, MM ;
Blenis, J .
CELL, 1996, 85 (04) :573-583
[10]   THE SMALL GTP-BINDING PROTEINS RAC1 AND CDC42 REGULATE THE ACTIVITY OF THE JNK/SAPK SIGNALING PATHWAY [J].
COSO, OA ;
CHIARIELLO, M ;
YU, JC ;
TERAMOTO, H ;
CRESPO, P ;
XU, NG ;
MIKI, T ;
GUTKIND, JS .
CELL, 1995, 81 (07) :1137-1146