Distinct Effects of the Mesenchymal Dysplasia Variant of Murine Patched-1 on Canonical and Non-canonical Hedgehog-signalling Pathways [Signal Transduction]

February 25th, 2014 by Harvey, M. C., Fleet, A., Okolowsky, N., Hamel, P. A.

Hedgehog (Hh) signalling requires regulation of the receptor, Patched-1 (Ptch1) that, in turn, regulates Smoothened activity (canonical Hh-signalling) as well as other non-canonical signalling pathways. The mutant Ptch1 allele, mesenchymal dysplasia (mes), which truncates the Ptch1 C-terminus, produces a limited spectrum of developmental defects in mice as well as deregulation of canonical Hh-signalling in some, but not all affected tissues. Paradoxically, mes suppresses canonical Hh-signalling and binds to Hh-ligands with an affinity similar to wild type mPtch1. We characterized the distinct activities of the mes variant of mPtch1 mediating Hh-signalling through both canonical and non-canonical pathways. We demonstrated that mPtch1 bound c-src in a Hh-regulated manner. Stimulation with Shh of primary mammary mesenchymal cells from wild type and mes animals activated Erk1/2. While Shh activated c-src in wild type cells, c-src was constitutively activated in mes mesenchymal cells. Transient assays showed that wild type mPtch1, mes, or mPtch1 lacking the C-terminus repressed Hh-signalling in Ptch1-deficient mouse embryo fibroblasts and that repression was reversed by Shh, revealing that the C-terminus was dispensable for mPtch1-dependent regulation of canonical Hh-signalling. In contrast to these transient assays, constitutively high levels of mGli1 but not mPtch1 were present in primary mammary mesenchymal cells from mes mice, while the expression of mPtch1 was similarly induced in both mes and wild type cells. These data define a novel signal transduction pathway involving c-src that is activated by the Hh-ligands and reveals the requirement for the C-terminus of Ptch in regulation of canonical and non-canonical Hh-signalling pathways.
  • Posted in Journal of Biological Chemistry, Publications
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