Interaction of PACAP with Sonic hedgehog reveals complex regulation of the Hedgehog pathway by PKA

Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (cGCPs) and its aberrant activation causes a cerebellar cancer medulloblastoma. Pituitary adenylate cyclase activating polypeptide (PACAP) inhibits Shh-driven proliferation of cGCPs and acts as tumor suppressor in murine medulloblastoma. We show that PACAP blocks canonical Shh signaling by a mechanism that involves activation of protein kinase A (PKA) and inhibition of the translocation of the Shh-dependent transcription factor Gli2 into the primary cilium. PICA is shown to play an essential role in inhibiting gene transcription in the absence of Shh, but global PICA activity levels are found to be a poor predictor of the degree of Shh pathway activation. We propose that the core Shh pathway regulates a small compartmentalized pool of PICA in the vicinity of primary cilia. GPCRs that affect global PICA activity levels, such as the PACAP receptor, cooperate with the canonical Shh signal to regulate Gli protein phosphorylation by PICA. This interaction serves to fine-tune the transcriptional and physiological function of the Shh pathway. (C) 2013 The Authors. Published by Elsevier Inc All rights reserved.