Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response

BenjaminR Myers, Navdar Sever, YongChun Chong, James Kim, JitendraD Belani, Scott Rychnovsky, J. Fernando Bazan, PhilipA Beachy

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Hedgehog (Hh) signaling during development and in postembryonic tissues requires activation of the 7TM oncoprotein Smoothened (Smo) by mechanisms that may involve endogenous lipidic modulators. Exogenous Smo ligands previously identified include the plant sterol cyclopamine (and its therapeutically useful synthetic mimics) and hydroxylated cholesterol derivatives (oxysterols); Smo is also highly sensitive to cellular sterol levels. The relationships between these effects are unclear because the relevant Smo structural determinants are unknown. We identify the conserved extracellular cysteine-rich domain (CRD) as the site of action for oxysterols on Smo, involving residues structurally analogous to those contacting the Wnt lipid adduct in the homologous Frizzled CRD; this modulatory effect is distinct from that of cyclopamine mimics, from Hh-mediated regulation, and from the permissive action of cellular sterol pools. These results imply that Hh pathway activity is sensitive to lipid binding at several Smo sites, suggesting mechanisms for tuning by multiple physiological inputs.

Original languageEnglish (US)
Pages (from-to)346-357
Number of pages12
JournalDevelopmental Cell
Volume26
Issue number4
DOIs
StatePublished - Aug 26 2013

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ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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