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

Sci. Signal., 21 August 2012
Vol. 5, Issue 238, p. ra60
DOI: 10.1126/scisignal.2002798

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

  1. Maarten F. Bijlsma1,2,
  2. Helene Damhofer2, and
  3. Henk Roelink1,*
  1. 1Department of Molecular and Cell Biology, University of California, Berkeley, 16 Barker Hall, 3204, Berkeley, CA 94720, USA.
  2. 2Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
  1. *To whom correspondence should be addressed. E-mail: roelink{at}berkeley.edu

Abstract

Regulation of the Hedgehog (Hh) pathway relies on an interaction of two receptors. In the absence of Hh, Patched1 (Ptch1) inhibits the pathway. Binding of the ligand Hh to Ptch1 stimulates the localization of the activating receptor Smoothened (Smo) to the primary cilium, which is required for the transcriptional Hh response. Hh can also induce chemotaxis through a nontranscriptional pathway. We assessed the effects of defective ciliary localization of Smo on its subcellular trafficking and ability to mediate chemotactic signaling. Cells expressing mutants of Smo that could not localize to the primary cilium or cells lacking the primary cilium showed altered intracellular trafficking of Smo and, in response to Hh or Smo agonists, decreased transcriptional signaling and enhanced chemotactic responsiveness. Thus, the ciliary localization machinery appears to transport Smo to subcellular 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 a pool of Smo dedicated to chemotaxis.

Citation:

M. F. Bijlsma, H. Damhofer, and H. Roelink, Hedgehog-Stimulated Chemotaxis Is Mediated by Smoothened Located Outside the Primary Cilium. Sci. Signal. 5, ra60 (2012).

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway
P. K. Dhanyamraju, P. S. Holz, F. Finkernagel, V. Fendrich, and M. Lauth
Molecular Cancer Therapeutics 14, 727-739 (1 March 2015)

Gas1 is a receptor for sonic hedgehog to repel enteric axons
S. Jin, D. C. Martinelli, X. Zheng, M. Tessier-Lavigne, and C.-M. Fan
Proc. Natl. Acad. Sci. USA 112, E73-E80 (6 January 2015)

Ptch2 mediates the Shh response in Ptch1-/- cells
A. C. Alfaro, B. Roberts, L. Kwong, M. F. Bijlsma, and H. Roelink
Development 141, 3331-3339 (1 September 2014)

Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling
A. Balic, M. D. Sorensen, S. M. Trabulo, B. Sainz, M. Cioffi, C. R. Vieira, I. Miranda-Lorenzo, M. Hidalgo, J. Kleeff, M. Erkan et al.
Molecular Cancer Therapeutics 13, 1758-1771 (1 July 2014)

Hedgehog: Multiple Paths for Multiple Roles in Shaping the Brain and Spinal Cord
J. Ferent, and E. Traiffort
Neuroscientist 0, 1073858414531457v2-1073858414531457 (8 May 2014)

Heparan Sulfate Proteoglycans Containing a Glypican 5 Core and 2-O-Sulfo-iduronic Acid Function as Sonic Hedgehog Co-receptors to Promote Proliferation
R. M. Witt, M.-L. Hecht, M. F. Pazyra-Murphy, S. M. Cohen, C. Noti, T. H. van Kuppevelt, M. Fuller, J. A. Chan, J. J. Hopwood, P. H. Seeberger et al.
J Biol Chem 288, 26275-26288 (6 September 2013)

Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened
T. Gorojankina, L. Hoch, H. Faure, H. Roudaut, E. Traiffort, A. Schoenfelder, N. Girard, A. Mann, F. Manetti, A. Solinas et al.
Mol. Pharmacol. 83, 1020-1029 (1 May 2013)

The Path to Chemotaxis and Transcription Is Smoothened
C. Lin, Y. I. Nozawa, and P.-T. Chuang
Sci Signal 5, pe35-pe35 (21 August 2012)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882