title: Interaction of PACAP with Sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA.
abstract: 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. PKA is shown to play an essential role in inhibiting gene transcription in the absence of Shh, but global PKA 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 PKA in the vicinity of primary cilia. GPCRs that affect global PKA activity levels, such as the PACAP receptor, cooperate with the canonical Shh signal to regulate Gli protein phosphorylation by PKA. This interaction serves to fine-tune the transcriptional and physiological function of the Shh pathway.
authors.affiliation: Intellectual Development and Disabilities Research Center, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Niewiadomski
authors.forename: Annie
authors.initials: A
authors.lastname: Zhujiang
authors.forename: Mary
authors.initials: M
authors.lastname: Youssef
authors.forename: James A
authors.initials: JA
authors.lastname: Waschek
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D014158:Transcription, Genetic; D000075746:Zinc Finger Protein Gli2
chemical_list: C495402:Adcyap1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C465570:Shh protein, mouse; D000075746:Zinc Finger Protein Gli2; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: 7-TM; 8-CPT; 8-CPT-2-Me-cAMPS; A-kinase anchoring protein; AC; AKAP; Bnz-cAMP; FSK; G-protein coupled receptor; G-protein coupled receptors; GPCR; Gli activator; Gli repressor; GliA; GliR; IBMX; MB; N-terminal fragment of Shh; N6-benzoyl-cAMP; PAC1 FI; PAC1-expressing flp-in NIH/3T3 cells; PACAP; PI3K; PKA; PKC; Patched; Primary cilia; Protein kinase A; Ptch; SDF-1; Shh; Shh-N; Smo; Smoothened; Sonic hedgehog; Stromal cell-derived factor 1; adenylate cyclase; cGCPs; cerebellar granule cell progenitors; forskolin; isobutylmethylxanthine; medulloblastoma; phosphoinositide-3 kinase; pituitary adenylate cyclase activating polypeptide; protein kinase A; protein kinase C; seven transmembrane domain