MEKK1 BINDS DIRECTLY TO THE C-JUN N-TERMINAL KINASES STRESS-ACTIVATEDPROTEIN-KINASES

Mitogen-activated protein (MAP) kinases mediate responses to a wide ar ray of cellular stimuli, These cascades consist of a MAP kinase or ext racellular signal-regulated kinase (ERK), activated by a MAP/ERK kinas e (MEK), in turn activated by a MEK kinase (MEKK). MEKK1 has been show n to be a strong activator of the c-Jun N-terminal kinase/stress-activ ed protein kinase (JNK/SAPK) pathway. We report here that JNK/SAPK bin ds directly to the N-terminal, noncatalytic domain of MEKK1 in vitro a nd in transfected cells. Immobilized MEKK1-derived peptides extract JN K/SAPK selectively from cell lysates. MEKK1 coimmunoprecipitates with multiple JNK/SAPK isoforms in transfected cells. Expression of the N t erminus of MEKK1 lacking the kinase domain increases activation of end ogenous JNK/SAPK by MEKK1. The data are consistent with a model in whi ch MEKK1-JNK/SAPK binding facilitates the receipt of signals from upst ream inputs and localizes JNK/SAPK to intracellular targets of the pat hway.