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J. Biol. Chem., Vol. 282, Issue 33, 24477-24484, August 17, 2007

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CD98hc (SLC3A2) Interaction with the Integrin Subunit Cytoplasmic Domain Mediates Adhesive Signaling^*

From the Department of Medicine, University of California San Diego, La Jolla, California 92093

In mammals, 1 integrin adhesion receptors generate signals that mediate cell spreading, migration, proliferation, and survival. CD98, a heterodimeric transmembrane protein, physically associates with certain integrin subunit cytoplasmic domains (tails) via its heavy chain, CD98hc (SLC3A2), and loss of CD98hc impairs integrin signaling. Here we have used the lack of CD98hc interaction with the Drosophila integrin PS tail for a homology scanning analysis that implicated the C-terminal 8 residues of 3 (Thr⁷⁵⁵-Thr⁸⁰²) in CD98hc binding. We then identified point mutations in the 3 C terminus (T755K and T758M) that abolish CD98hc association and a double mutation in the corresponding residues in the PS tail (K839T,M842T), which resulted in gain of CD98hc interaction. Furthermore, the loss of function 3(T755K) mutation or the gain of function 3/PS(K839T,M842T) led to a loss or gain of integrin-mediated cell spreading, respectively. Thus, we have identified critical integrin residues required for CD98hc interaction and in doing so have shown that CD98c interaction with the integrin tail is required for its ability to mediate integrin signaling. These studies also provide new insights into how CD98hc may cooperate with other cytoplasmic domain binding proteins to modulate integrin functions and into the evolution of integrin signaling.

Received for publication, April 4, 2007 , and in revised form, June 20, 2007.

^* This work was supported in part by Austrian Science Foundation Fellowship J2511-B11 (to G. W. P.), National Institutes of Health Grants HL078784, AR27214, and HL31950, and by Cell Migration Consortium Grant U54 GM064346. 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: University of California, Leichtag Bldg., Rm. 181, 9500 Gilman Dr., Dept. 0726, La Jolla, CA 92093-0726. Tel.: 858-822-6432; Fax: 858-822-6458; E-mail: mhginsberg{at}ucsd.edu.

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