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J. Biol. Chem., Vol. 282, Issue 41, 30322-30330, October 12, 2007

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Intrinsic Signaling Functions of the 4 Integrin Intracellular Domain^*

From the Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

A key issue regarding the role of 64 in cancer biology is the mechanism by which this integrin exerts its profound effects on intracellular signaling, including growth factor-mediated signaling. One approach is to evaluate the intrinsic signaling capacity of the unique 4 intracellular domain in the absence of contributions from the 6 subunit and tetraspanins and to assess the ability of growth factor receptor signaling to cooperate with this domain. Here, we generated a chimeric receptor composed of the TrkB extracellular domain and the 4 transmembrane and intracellular domains. Expression of this chimeric receptor in 4-null cancer cells enabled us to assess the signaling potential of the 4 intracellular domain alone or in response to dimerization using brain-derived neurotrophic factor, the ligand for TrkB. Dimerization of the 4 intracellular domain results in the binding and activation of the tyrosine phosphatase SHP-2 and the activation of Src, events that also occur upon ligation of intact 64. In contrast to 64 signaling, however, dimerization of the chimeric receptor does not activate either Akt or Erk1/2. Growth factor stimulation induces tyrosine phosphorylation of the chimeric receptor but does not enhance its binding to SHP-2. The chimeric receptor is unable to amplify growth factor-mediated activation of Akt and Erk1/2, and growth factor-stimulated migration. Collectively, these data indicate that the 4 intracellular domain has some intrinsic signaling potential, but it cannot mimic the full signaling capacity of 64. These data also question the putative role of the 4 intracellular domain as an "adaptor" for growth factor receptor signaling.

Received for publication, April 13, 2007 , and in revised form, August 15, 2007.

^* This work was supported by National Institutes of Health Grants CA80789 (to A. M. M.) and F32CA117746 (to K. D. M.) and American Cancer Society Research Scholar Grant RSG-05-223-01 (to L. M. S.). 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: Dept. of Cancer Biology, University of Massachusetts Medical School, LRB-408, 364 Plantation St., Worcester, MA 01605. Tel.: 508-856-8676; Fax: 508-856-1310; E-mail: arthur.mercurio{at}umassmed.edu.

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