Hedgehog-Stimulated Chemotaxis Is Mediated by Smoothened Located Outside the Primary Cilium

Abstract

Regulation of the Hedgehog (Hh) pathway relies on an interaction of two receptors that is not fully understood. Patched1 (Ptch1) binds the Hh ligand, but is also a negative regulator of pathway activity. Binding of Hh ligand to Ptch1 leads to the relocation of the activating receptor Smoothened (Smo) to the primary cilium, which is required for the transcriptional Hh response. Besides the transcriptional response, Hh can also induce chemotaxis, and we assessed the effects of defective ciliary localization of Smo on its subcellular itineraries and chemotactic signaling capacity. We find that defective ciliary localization of Smo results in markedly different intracellular trafficking of Smo to sites not involving the primary cilium. These itineraries correlate with a decreased transcriptional signaling capacity, and an enhanced chemotactic responsiveness. These data imply that the ciliary localization machinery functions to transport Smo to sites where it can mediate transcriptional signaling, and away from locations where it can mediate chemotactic signaling. The subcellular localization of Smo is thus a crucial determinant of its signaling characteristics and implies the existence of pool of Smo dedicated to chemotaxis.

Heparan Sulfate Proteoglycans Containing a Glypican 5 Core and 2-O-Sulfo-iduronic Acid Function as Sonic Hedgehog Co-receptors to Promote Proliferation

“…In this way, the proteoglycan receptor may alter the kinetics or intensity of Shh signaling (23) and thereby augment the biological response (57). The localization of proteoglycan receptors adjacent to primary cilia is consistent with evidence that these co-receptors contribute to transcriptional and proliferative responses to Shh and may play a lesser role in functions independent of the primary cilia such as chemotaxis and neurite outgrowth (33).…”

Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened

“…This feature questions the proposed theory according to which Smo localization to the cilium is necessary (but not sufficient) for activation of the Hh pathway (Wilson et al, 2009). In agreement with this questioning, the Shhmediated chemotactic response that requires neither de novo gene transcription nor Gli protein functions was found to be mediated by Smo located outside the primary cilium (Chinchilla et al, 2010;Bijlsma et al, 2012).…”

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

“…This observation warrants further investigation as it could be used to circumvent unwanted side effects associated with blocking Hh-dependent physiologic processes. In addition, an unexplored question as of now is whether HDAC6 inhibition affects SMO-dependent, but GLI-independent noncanonical signaling (65,66).…”