CD98hc (SLC3A2) mediates integrin signaling

doi:10.1073/pnas.0404852102

CD98hc (SLC3A2) mediates integrin signaling

^*Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037; and ^†Department of Medicine, University of California, San Diego, La Jolla, CA 92093

Edited by Barry S. Coller, The Rockefeller University, New York, NY (received for review July 6, 2004)

Abstract

Integrins regulate cellular behaviors through signaling pathways, including Rho GTPases and kinases. CD98 heterodimers, comprised of a heavy chain (CD98hc, SLC3A2) and one of several light chains, interact with integrins through CD98hc. CD98hc overexpression leads to anchorage-independent cell growth and tumorigenesis in 3T3 fibroblasts and activates certain integrin-regulated signaling pathways. To establish the biological function of CD98hc, we disrupted the gene and analyzed CD98hc-null cells. Here we report that CD98hc contributes to integrin-dependent cell spreading, cell migration, and protection from apoptosis. Furthermore, CD98hc is required for efficient adhesion-induced activation of Akt and Rac GTPase, major contributors to the integrin-dependent signals involved in cell survival and cell migration. CD98 promotes amino acid transport through its light chains; however, a CD98hc mutant that interacts with β1 integrins, but not CD98 light chains, restored integrin-dependent signaling and protection from apoptosis. β1 integrins are involved in the pathogenesis of certain cancers. CD98hc deletion markedly impaired the ability of embryonic stem cells to form teratocarcinomas in mice; teratocarcinoma formation was reconstituted by reexpression of CD98hc or of the mutant that interacts exclusively with integrins. Thus, CD98hc is an integrin-associated protein that mediates integrin-dependent signals, which promote tumorigenesis.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: mhginsberg{at}ucsd.edu
Author contributions: C.C.F. and M.H.G. designed research; C.C.F., N.N., and M.S. performed research; C.A.F. and M.H.G. contributed new reagents/analytic tools; C.C.F. and M.H.G. analyzed data; and C.C.F. and M.H.G. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: EB, embryoid bodies; FAK, focal adhesion kinase; Fn, fibronectin; Ln, laminin-1; PI, propidium iodide; PI3-kinase, phosphatidylinositol 3-kinase.