Hedgehog activates fused through phosphorylation to elicit a full spectrum of pathway responses

Dev Cell. 2011 Jun 14;20(6):802-14. doi: 10.1016/j.devcel.2011.04.020.

Abstract

In flies and mammals, extracellular Hedgehog (Hh) molecules alter cell fates and proliferation by regulating the levels and activities of Ci/Gli family transcription factors. How Hh-induced activation of transmembrane Smoothened (Smo) proteins reverses Ci/Gli inhibition by Suppressor of Fused (SuFu) and kinesin family protein (Cos2/Kif7) binding partners is a major unanswered question. Here we show that the Fused (Fu) protein kinase is activated by Smo and Cos2 via Fu- and CK1-dependent phosphorylation. Activated Fu can recapitulate a full Hh response, stabilizing full-length Ci via Cos2 phosphorylation and activating full-length Ci by antagonizing Su(fu) and by other mechanisms. We propose that Smo/Cos2 interactions stimulate Fu autoactivation by concentrating Fu at the membrane. Autoactivation primes Fu for additional CK1-dependent phosphorylation, which further enhances kinase activity. In this model, Smo acts like many transmembrane receptors associated with cytoplasmic kinases, such that pathway activation is mediated by kinase oligomerization and trans-phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Casein Kinase I / genetics
  • Casein Kinase I / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism*
  • Female
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Immunoenzyme Techniques
  • Kinesin / genetics
  • Kinesin / metabolism*
  • Male
  • Mutagenesis
  • Phosphorylation
  • Plasmids
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Smoothened Receptor
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Hedgehog Proteins
  • Receptors, G-Protein-Coupled
  • Smoothened Receptor
  • Transcription Factors
  • ci protein, Drosophila
  • cos protein, Drosophila
  • smo protein, Drosophila
  • fu protein, Drosophila
  • Casein Kinase I
  • Protein-Serine-Threonine Kinases
  • Kinesin