CREB-regulated transcription coactivator 2 (transducer of regulated cAMP response element-binding protein 2, TORC-2, transducer of CREB protein 2, CRTC2, TORC2)

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 a) TORCs are inactive when phosphorylated, & active when dephosphorylated at this site b) this primary site of phosphorylation, is regulated by cAMP & Ca⁺² levels & is dependent on the phosphorylation of SIKs by LKB1 c) 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)

General

CREB-regulated transcription coactivator (transducer of regulated cAMP response element-binding protein, transducer of CREB protein, CRTC) phosphoprotein

Properties

SIZE: entity length = 693 aa MW = 73 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: Ser phosphorylation site {S70} Ser phosphorylation site {S90} Ser phosphorylation site {S136} Thr phosphorylation site {T169} Ser phosphorylation site {S171} Thr phosphorylation site {T177} serine-rich region {236-240} MOTIF: serine residue (SEVERAL) nuclear export signal {271-287} Ser phosphorylation site {S306} serine-rich region {336-408} MOTIF: serine residue (SEVERAL) Ser phosphorylation site {S368} Ser phosphorylation site {S393} Ser phosphorylation site {S433} Ser phosphorylation site {S456} Ser phosphorylation site {S489} Ser phosphorylation site {S492} Ser phosphorylation site {S613} lysine residue {629}

References

UniProt :accession Q53ET0