CREB-regulated transcription coactivator 2 (transducer of regulated cAMP response element-binding protein 2, TORC-2, transducer of CREB protein 2, CRTC2, TORC2)
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Function
- transcriptional coactivator for CREB1 which activates transcription through both consensus & variant cAMP response element (CRE) sites
- acts as a coactivator, in the SIK/TORC signaling pathway, being active when dephosphorylated & acts independently of CREB1 Ser-133 phosphorylation
- enhances interaction of CREB1 with TAF4
- regulates gluconeogenesis as a component of the LKB1/AMPK/TORC2 signaling pathway
- regulates expression of specific genes such as the steroidogenic gene, StAR
- potent coactivator of PPARGC1A & inducer of mitochondrial biogenesis in muscle cells
- binds, as a tetramer, through its N-terminal region, with the bZIP domain of CREB1, Arg-314 in the bZIP domain of CREB1 is essential for this interaction
- interaction, via its C-terminal, with TAF4, enhances recruitment of TAF4 to CREB1 (putative)
- interacts with PPP3CA/calcineurin alpha, SNF1LK2 & 14-3-3 proteins, YWHAB & YWHAG
- interaction with RFWD2/COP1 mediates nuclear export & degradation of TORC2
- phosphorylation/dephosphorylation states of Ser-171 are required for regulating transduction of CREB activity
- TORCs are inactive when phosphorylated, & active when dephosphorylated at this site
- this primary site of phosphorylation, is regulated by cAMP & Ca+2 levels & is dependent on the phosphorylation of SIKs by LKB1
- both insulin & AMPK increase this phosphorylation of TORC2 while glucagon suppresses it
Structure
belongs to the TORC family
Compartment
- cytoplasm, nucleus
- translocated from nucleus to cytoplasm on interaction of phosphorylated form with 14-3-3 protein
- in response to cAMP levels & glucagon, relocated to nucleus
Expression
- most abundantly expressed in the thymus
- present in both B & T lymphocytes
- high levels also in spleen, ovary, muscle & lung, with highest levels in muscle
- lower levels found in brain, colon, heart, kidney, prostate, small intestine & stomach
- weak expression in liver & pancreas
Pathology
- coactivator for TAX activation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeats (LTR)
- interaction with the human T-cell leukemia virus type 1 (HTLV-1) Tax protein is essential for optimal transcription activation by Tax
- highly expressed in HEK293T cells & in insulinomas
Polymorphism
- variant Cys-379, under a dominant model, linked to a recessive mutation in LKB1, may be associated with susceptibility to type 2 diabetes mellitus (NIDDM)