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J. Biol. Chem., Vol. 282, Issue 9, 6899-6905, March 2, 2007

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MT1-MMP Controls Tumor-induced Angiogenesis through the Release of Semaphorin 4D^*

John R. Basile¹, Kenn Holmbeck, Thomas H. Bugge, and J. Silvio Gutkind

From the Oral and Pharyngeal Cancer Branch and Matrix Metalloproteinase Unit, NIDCR, National Institutes of Health, Bethesda, Maryland 20892

The semaphorins are a family of proteins originally identified as regulators of axon growth that recently have been implicated in blood vessel development. The plexins are high affinity receptors for the semaphorins and are responsible for initiation of signaling upon ligation. Emerging evidence indicates that many human cancers overexpress Semaphorin 4D, which promotes neovascularization upon stimulating its receptor, Plexin-B1, on endothelial cells. However, to exert its pro-angiogenic functions, Semaphorin 4D must be processed and released from its membrane bound form to act in a paracrine manner on endothelial cells. Here we show that Semaphorin 4D is a novel target for the membrane-tethered collagenase membrane type 1-matrix metalloproteinase. We demonstrate that this metalloproteinase, which is not expressed in normal or immortal but non-tumorigenic epithelial cell lines, was present in several head and neck squamous cell carcinoma cell lines and was required for processing and release of Semaphorin 4D into its soluble form from these cells, thereby inducing endothelial cell chemotaxis in vitro and blood vessel growth in vivo. These results suggest that the proteolytic cleavage of Semaphorin 4D may provide a novel molecular mechanism by which membrane type 1-matrix metalloproteinase controls tumor-induced angiogenesis.

Received for publication, October 11, 2006 , and in revised form, January 4, 2007.

^* This work was supported by the Intramural Research Program of the National Institutes of Health, NIDCR. 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.

¹ To whom correspondence should be addressed: Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, 30 Convent Dr., Rm. 211, Bethesda, MD 20892. Tel.: 301-496-3695; Fax: 301-402-0823; E-mail: jbasile{at}mail.nih.gov.

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