EMAIL THIS PAGE TO A FRIEND

Chemistry & biology

The Hedgehog pathway effector smoothened exhibits signaling competency in the absence of ciliary accumulation.


PMID 25484239

Abstract

Misactivation of the seven-transmembrane protein Smoothened (Smo) is frequently associated with basal cell carcinoma and medulloblastoma. Cellular exposure to secreted Hedgehog (Hh) protein or oncogenic mutations in Hh pathway components induces Smo accumulation in the primary cilium, an antenna-like organelle with mostly unknown cellular functions. Despite the data supporting an indispensable role of the primary cilium in Smo activation, the mechanistic underpinnings of this dependency remain unclear. Using a cell-membrane-impermeable Smo antagonist (IHR-1), we demonstrate that Smo supplied with a synthetic agonist or activated with oncogenic mutations can signal without ciliary accumulation. Similarly, cells with compromised ciliary Smo trafficking due to loss of the phosphatidylinositol-4-phosphate 3-kinase (PI3K)-C2α retain transcriptional response to an exogenously supplied Smo agonist. These observations suggest that assembly of a Smo-signaling complex in the primary cilium is not a prerequisite for Hh pathway activationxa0driven by Smo agonists or oncogenic Smo molecules.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

SML1363
IHR-1, ≥98% (HPLC)
C20H12Cl4N2O2