MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42

被引:251
作者
Fanger, GR
Johnson, NL
Johnson, GL
机构
[1] NATL JEWISH MED & RES CTR,PROGRAM MOL SIGNAL TRANSDUCT,DENVER,CO 80206
[2] UNIV COLORADO,SCH MED,DEPT PHARMACOL,DENVER,CO 80262
关键词
Cdc42; epidermal growth factor; MEK kinases; Rac; subcellular distribution;
D O I
10.1093/emboj/16.16.4961
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
MEK kinases (MEKKs) 1, 2, 3 and 4 are members of sequential kinase pathways that regulate MAP kinases including c-Jun NH2-terminal kinases (JNKs) and extracellular regulated kinases (ERKs), Confocal immunofluorescence microscopy of COS cells demonstrated differential MEKK subcellular localization: MEKK1 was nuclear and in post-Golgi vesicular-like structures; MEKK2 and 4 were localized to distinct Golgi-associated vesicles that were dispersed by brefeldin A, MEKK1 and 2 were activated by EGF, and kinase-inactive mutants of each MEKK partially inhibited EGF-stimulated JNK activity, Kinase-inactive MEKK1, but not MEKK2, 3 or 4, strongly inhibited EGF-stimulated ERK activity, In contrast to MEKK2 and 3, MEKK1 and 4 specifically associated with Pac and Cdc42 and kinase-inactive mutants blocked Rac/Cdc42 stimulation of JNK activity, Inhibitory mutants of MEKK1-4 did not affect p21-activated kinase (PAK) activation of JNK, indicating that the PAK-regulated JNK pathway is independent of MEKKs, Thus, in different cellular locations, specific MEKKs are required for the regulation of MAPK family members, and MEKK1 and 4 are involved in the regulation of JNK activation by Rac/Cdc42 independent of PAK. Differential MEKK subcellular distribution and interaction with small GTP-binding proteins provides a mechanism to regulate MAP kinase responses in localized regions of the cell and to different upstream stimuli.
引用
收藏
页码:4961 / 4972
页数:12
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