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

Shuang Li, Guoqiang Ma, Bing Wang, Jin Jiang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Hedgehog (Hh) is a secreted glycoprotein that binds its receptorPatched to activate theGprotein (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 fromthe 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 uncharacterizedmechanismfor regulation of PKA activity and demonstrates that the signal-regulated formation of kinase-substrate complexes plays a central role in Hh signal transduction.

Original languageEnglish (US)
Article numberra62
JournalScience Signaling
Volume7
Issue number332
DOIs
StatePublished - Jul 1 2014

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Phosphorylation
Hedgehogs
Cyclic AMP-Dependent Protein Kinases
Chemical activation
Phosphotransferases
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
Association reactions
Kinesin
Signal transduction
Guanine Nucleotides
Substrates
Dimers
Glycoproteins
Carrier Proteins
Proteins
Transcription Factors
Drosophila
Switches
Signal Transduction
Membranes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Hedgehog induces formation of PKA-smoothened complexes to promote smoothened phosphorylation and pathway activation. / Li, Shuang; Ma, Guoqiang; Wang, Bing; Jiang, Jin.

In: Science Signaling, Vol. 7, No. 332, ra62, 01.07.2014.

Research output: Contribution to journalArticle

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