Research ArticleDevelopmental Biology

Hedgehog induces formation of PKA-Smoothened complexes to promote Smoothened phosphorylation and pathway activation

See allHide authors and affiliations

Sci. Signal.  01 Jul 2014:
Vol. 7, Issue 332, pp. ra62
DOI: 10.1126/scisignal.2005414

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Abstract

Hedgehog (Hh) is a secreted glycoprotein that binds its receptor Patched to activate the G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor–like protein Smoothened (Smo). In Drosophila, protein kinase A (PKA) phosphorylates and activates Smo in cells stimulated with Hh. In unstimulated cells, PKA phosphorylates and inhibits the transcription factor Cubitus interruptus (Ci). We found that in cells exposed to Hh, the catalytic subunit of PKA (PKAc) bound to the juxtamembrane region of the carboxyl terminus of Smo. PKA-mediated phosphorylation of Smo further enhanced its association with PKAc to form stable kinase-substrate complexes that promoted the PKA-mediated transphosphorylation of Smo dimers. We identified multiple basic residues in the carboxyl terminus of Smo that were required for interaction with PKAc, Smo phosphorylation, and Hh pathway activation. Hh induced a switch from the association of PKAc with a cytosolic complex of Ci and the kinesin-like protein Costal2 (Cos2) to a membrane-bound Smo-Cos2 complex. Thus, our study uncovers a previously uncharacterized mechanism for regulation of PKA activity and demonstrates that the signal-regulated formation of kinase-substrate complexes plays a central role in Hh signal transduction.

View Full Text