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

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Abstract
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 Rac 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.