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J. Biol. Chem., Vol. 281, Issue 45, 33860-33870, November 10, 2006

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Molecular Pathways Regulating Pro-migratory Effects of Hedgehog Signaling^*

From the Research Section of Childhood Malignancies, Sheba Cancer Research Center, Safra Children Hospital, Sheba Medical Center and Faculty of Medicine, Tel-Aviv University, Tel Hashomer 52621, Israel

The Hedgehog proteins play a crucial role in metazoan embryo development. Constitutive activation of the pathway is associated with multiple types of cancer. Recent experimental data suggest involvement of Hedgehog signaling in vascular remodeling, germ cell migration, and axon guidance. The molecular mechanisms underlying these effects remain elusive. Here we show that yolk sac-derived endothelial cells and embryonic fibroblasts can directly respond to the Hedgehog signal by increased migration in an in vitro scratch (wound) assay. We also identify Hedgehog transcriptional target genes in these cells, many of which participate in cell migration, axon guidance, and angiogenesis processes. Inhibition of one such molecular pathway, neuropilin-flavomonooxygenase, blocks Hedgehog-induced cell migration. These findings suggest that Hedgehog signaling directly affects embryonic endothelial and fibroblast cell migration via molecules and pathways known to regulate cell migration in response to a variety of environmental cues.

Received for publication, June 20, 2006 , and in revised form, August 29, 2006.

^* This work was supported in part by the Israel Science Foundation, The Leukemia Research Foundation, The Israel Cancer Research Foundation, and The Recannati Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and supplemental Figs. 1 and 2.

¹ Performed this work in partial fulfillment of the requirements for the M.D.-Ph.D. thesis at Sackler Faculty of Medicine, Tel Aviv University, Israel.

² To whom correspondence should be addressed. E-mail: sizraeli{at}sheba.health.gov.il.

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