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Vol. 19, Issue 11, 4750-4761, November 2008

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Activation of TORC1 Transcriptional Coactivator through MEKK1-induced Phosphorylation

Yeung-Tung Siu^*, Yick-Pang Ching, and Dong-Yan Jin^*

*Department of Biochemistry and Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong

Submitted April 9, 2008; Revised August 19, 2008; Accepted August 28, 2008
Monitoring Editor: Benjamin Margolis

CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431–650 of TORC1. As a physiological activator of CREB, interleukin 1 triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling.

Address correspondence to: Dong-Yan Jin (dyjin{at}hkucc.hku.hk)