TGF and#946; Activated Kinase 1 TAK1 mediated crosstalk through mTOR pathway

Abstract

TGF-and#946; Activated kinase 1 (TAK1), a ubiquitously expressed serine threonine kinase was first identified as a member of the MAPK kinase kinase (MAP3K) family newlineactivated by TGF-and#946;1. TAK1 is a widely expressed kinase activated by various other newlinestimuli including lipopolysaccharides, pro-inflammatory cytokines like interleukin newline(IL)-1, tumor necrosis factor (TNF)-and#945; and environmental stress. TGF-and#946; activated newlinekinase 1 has been implicated in regulating a wide range of cellular processes that newlineinclude embryonic development, autophagy, apoptosis, differentiation and cell newlinesurvival. TAK1 along with its binding partners TAK1 binding protein 1 (TAB1), newlineTAK1 binding protein 2 (TAB2) and TAK1 binding protein 3 (TAB3) displays a newlinecomplex pattern of regulation that includes serious crosstalk with major signaling newlinepathways including the c-Jun N-terminal kinase (JNK), p38 MAPK and I-kappa B newlinekinase complex (IKK) etc involved in establishing cellular commitments for death newlineand survival. TAK1 orchestrates regulation of energy homeostasis via AMPK and its newlinerelevance in regulation of mTORC1 pathway to emerge as a key player in modulating newlinecell death and survival. newlineIn an attempt to proximate TAK1 and mTORC1, we first established a possible newlineconnection between the two entities and demonstrate that TAK1 associated with a newlinemajor mTORC1 substrate S6K1. We further show that TAK1 binding to S6K1 is newlinerestricted to its catalytic domain that couples with the increase in phosphorylation at Thr-412 and corroborates with TAK1 mediated stimulation of S6K1 activity. We newlinefurther show that TAK1 dependent activation of S6K1 does not exclusively target newlineThr-412 phosphorylation to suggest a collaboration of kinases other than mTORC1 as newlineregulatory partners for TAK1. This was substantiated by the observation that TAK1 newlinedependent activation of S6K1 is not affected by rapamycin or raptor. We also newlinesubstantiate that TAK1 interaction was specific for S6K1 as no detectable interaction of TAK1 was observed with 4E-BP1 - another mTORC1 substrate to discount the involvement of raptor...