Figure 10. Diagram representing the signaling pathways regulating TORC translocation to the nucleus and activation of CRH transcription.

In basal conditions TORC is in the cytoplasm, in an inactive state phosphorylated at Ser 171 and bound to the scaffolding protein 14-3-3. Based on the described effect of the phorbol ester, PMA, on TORC phosphorylation, and known ability of salt inducible kinase (SIK) to phosphorylate TORC, it is likely that protein kinase C (PKC) activates SIK, which in turn maintains TORC phosphorylated in the cytoplasm. Stimulation of adenylate cyclase (AC) by forskolin or a G-protein coupled receptor (not shown) leads to cyclic AMP production and stimulation of protein kinase A (PKA), which phosphorylates SIK at Ser 577 and inactivates it, blocking TORC phosphorylation. In addition, increase in intracellular calcium stimulates the phosphatase, calcineurin (PPP3), which has been shown to dephosphorylate TORC. Upon dephosphorylation, TORC dissociates from 14-3-3 nad translocates to the nucleus (indicated by the green dotted lines) where it interacts with CREB at the cyclic AMP response element in the CRH promoter and facilitates the recruitment the transcription initiation complex including CREB binding protein (CBP)/p300, TATA binding protein (TBP), TBP associated factors (TAFII) and RNA polymerase II (Pol II).