Ptch2 mediates the Shh response in Ptch1−/− cells

Citations Over TimeTop 11% of 2014 papers

Abstract

The Hedgehog (Hh) signaling response is regulated by the interaction of three key components that include the sonic hedgehog (Shh) ligand, its receptor patched 1 (Ptch1) and the pathway activator smoothened (Smo). Under the prevailing model of Shh pathway activation, the binding of Shh to Ptch1 (the key Shh receptor) results in the release of Ptch1-mediated inhibition of Smo, leading to Smo activation and subsequent cell-autonomous activation of the Shh response. Consistent with this model, Ptch1(-/-) cells show a strong upregulation of the Shh response. Our finding that this response can be inhibited by the Shh-blocking antibody 5E1 indicates that the Shh response in Ptch1(-/-) cells remains ligand dependent. Furthermore, we find that Shh induces a strong response in Ptch1(-/-);Shh(-/-) cells, and that Ptch1(-/-) fibroblasts retain their ability to migrate towards Shh, demonstrating that Ptch1(-/-) cells remain sensitive to Shh. Expression of a dominant-negative Ptch1 mutant in the developing chick neural tube had no effect on Shh-mediated patterning, but expression of a dominant-negative form of patched 2 (Ptch2) caused an activation of the Shh response. This indicates that, at early developmental stages, Ptch2 functions to suppress Shh signaling. We found that Ptch1(-/-);Ptch2(-/-) cells cannot further activate the Shh response, demonstrating that Ptch2 mediates the response to Shh in the absence of Ptch1.

Related Papers

• → The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog(1996)1,110 cited
• → Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma(2009)1,108 cited
• → Structural basis for the recognition of Sonic Hedgehog by human Patched1(2018)225 cited
• → Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex(2018)132 cited
• → The first step in Hedgehog signaling(2018)