Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites.
Sonic hedgehog (Shh) is a morphogen pivotal for development and tissue maintenance. Biological effects of Shh are mediated through a pathway that involves binding to patched1 (Ptch1), thereby releasing Smoothened (Smo) from inhibition resulting in the activation of Gli transcription factors, which mediate the induction of Shh target genes. Here, we describe a novel signal transduction pathway for Shh, which is transcription/translation-independent, SuFu insensitive, and consequently independent of Gli-mediated induction of transcription. Through this alternative pathway Shh, transduced via Smo, induced altered cell morphology together with lamellipodia formation. Migration assays demonstrate that this cytoskeletal rearrangement mediates the migratory response to Shh. This Shh-induced, Smo mediated migration utilizes and requires the metabolism of arachidonic acid through the 5-lipoxygenase pathway. These data provide a link between a seemingly novel Gli-independent Hh signaling pathway and the leukotriene metabolism, and might explain the developmental abnormalities observed in both patients with defective leukotriene metabolism as well as in rodent models of defective Rho family GTPase signaling.
Bijlsma
Maarten F
MF
Center for Experimental and Molecular Medicine, Room G2-105, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. m.f.bijlsma@amc.uva.nl
Borensztajn
Keren S
KS
Roelink
Henk
H
Peppelenbosch
Maikel P
MP
Spek
C Arnold
CA
D000199:Actins / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D048430:Cell Shape; D002633:Chemotaxis; D003599:Cytoskeleton / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D007700:Kinetics; D015289:Leukotrienes / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000071676:Zinc Finger Protein GLI1
D000199:Actins; D053823:Hedgehog Proteins; D015289:Leukotrienes; D015513:Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D012097:Repressor Proteins; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase