QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 01-11-0530v1 13/8/2841    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rintoul, R. C. Articles by Sethi, T. Search for Related Content PubMed PubMed Citation Articles by Rintoul, R. C. Articles by Sethi, T.

Vol. 13, Issue 8, 2841-2852, August 2002

Cross-Linking CD98 Promotes Integrin-like Signaling and Anchorage-independent Growth

Robert C. Rintoul,^* Robert C. Buttery,^* Alison C Mackinnon,^* Weng Sie Wong,^* Deane Mosher, Christopher Haslett,^* and Tariq Sethi^*§

 ^*Lung Inflammation Group, Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom; and  Departments of Medicine and Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53706

CD98, an early marker of T-cell activation, is an important regulator of integrin-mediated adhesion events. Previous studies suggest that CD98 is coupled to both cellular activation and transformation and is involved in the pathogenesis of viral infection, inflammatory disease, and cancer. Understanding of the molecular mechanisms underlying CD98 activity may have far-reaching practical applications in the development of novel therapeutic strategies in these disease states. Using small cell lung cancer cell lines, which are nonadherent, nonpolarized, and highly express CD98, we show that, in vitro, under physiological conditions, CD98 is constitutively associated with 1 integrins regardless of activation status. Cross-linking CD98 with the monoclonal antibody 4F2 stimulated phosphatidylinositol (PI) 3-kinase, PI(3,4,5)P₃, and protein kinase B in the absence of integrin ligation or extracellular matrix engagement. Furthermore, cross-linking CD98 promoted anchorage-independent growth. Using fibroblasts derived from 1 integrin null stem cells (GD25), wild-type GD251, or GD25 cells expressing a mutation preventing 1 integrin-dependent FAK phosphorylation, we demonstrate that a functional 1 integrin is required for CD98 signaling. We propose that by cross-linking CD98, it acts as a "molecular facilitator" in the plasma membrane, clustering 1 integrins to form high-density complexes. This results in integrin activation, integrin-like signaling, and anchorage-independent growth. Activation of PI 3-kinase may, in part, explain cellular transformation seen on overexpressing CD98. These results may provide a paradigm for events involved in such diverse processes as inflammation and viral-induced cell fusion.

---

R.C.R. and R.C.B. contributed equally to this work.

^§ Corresponding author. E-mail address: t.sethi{at}ed.ac.uk.

---

Molecular Biology of the Cell
Vol. 13, 2841-2852, August 2002
Copyright © 2002 by The American Society for Cell Biology

This article has been cited by other articles:

				M. V. Veettil, S. Sadagopan, N. Sharma-Walia, F.-Z. Wang, H. Raghu, L. Varga, and B. Chandran Kaposi's Sarcoma-Associated Herpesvirus Forms a Multimolecular Complex of Integrins ({alpha}V{beta}5, {alpha}V{beta}3, and {alpha}3{beta}1) and CD98-xCT during Infection of Human Dermal Microvascular Endothelial Cells, and CD98-xCT Is Essential for the Postentry Stage of Infection J. Virol., December 15, 2008; 82(24): 12126 - 12144. [Abstract] [Full Text] [PDF]

				A. C. MacKinnon, S. L. Farnworth, P. S. Hodkinson, N. C. Henderson, K. M. Atkinson, H. Leffler, U. J. Nilsson, C. Haslett, S. J. Forbes, and T. Sethi Regulation of Alternative Macrophage Activation by Galectin-3 J. Immunol., February 15, 2008; 180(4): 2650 - 2658. [Abstract] [Full Text] [PDF]

				G. W. Prager, C. C. Feral, C. Kim, J. Han, and M. H. Ginsberg CD98hc (SLC3A2) Interaction with the Integrin beta Subunit Cytoplasmic Domain Mediates Adhesive Signaling J. Biol. Chem., August 17, 2007; 282(33): 24477 - 24484. [Abstract] [Full Text] [PDF]

				A. Schubert-Unkmeir, O. Sokolova, U. Panzner, M. Eigenthaler, and M. Frosch Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis Infect. Immun., February 1, 2007; 75(2): 899 - 914. [Abstract] [Full Text] [PDF]

				H. Abdala-Valencia and J. M. Cook-Mills VCAM-1 Signals Activate Endothelial Cell Protein Kinase C{alpha} via Oxidation J. Immunol., November 1, 2006; 177(9): 6379 - 6387. [Abstract] [Full Text] [PDF]

				E. Fernandez, M. Jimenez-Vidal, M. Calvo, A. Zorzano, F. Tebar, M. Palacin, and J. Chillaron The Structural and Functional Units of Heteromeric Amino Acid Transporters: THE HEAVY SUBUNIT rBAT DICTATES OLIGOMERIZATION OF THE HETEROMERIC AMINO ACID TRANSPORTERS J. Biol. Chem., September 8, 2006; 281(36): 26552 - 26561. [Abstract] [Full Text] [PDF]

				A. Thelemann, F. Petti, G. Griffin, K. Iwata, T. Hunt, T. Settinari, D. Fenyo, N. Gibson, and J. D. Haley Phosphotyrosine Signaling Networks in Epidermal Growth Factor Receptor Overexpressing Squamous Carcinoma Cells Mol. Cell. Proteomics, April 1, 2005; 4(4): 356 - 376. [Abstract] [Full Text] [PDF]

				S. Cai, N. Bulus, P. M. Fonseca-Siesser, D. Chen, S. K. Hanks, A. Pozzi, and R. Zent CD98 modulates integrin {beta}1 function in polarized epithelial cells J. Cell Sci., March 1, 2005; 118(5): 889 - 899. [Abstract] [Full Text] [PDF]

				C. C. Feral, N. Nishiya, C. A. Fenczik, H. Stuhlmann, M. Slepak, and M. H. Ginsberg CD98hc (SLC3A2) mediates integrin signaling PNAS, January 11, 2005; 102(2): 355 - 360. [Abstract] [Full Text] [PDF]

				N. C. Henderson, E. A. Collis, A. C. Mackinnon, K. J. Simpson, C. Haslett, R. Zent, M. Ginsberg, and T. Sethi CD98hc (SLC3A2) Interaction with {beta}1 Integrins Is Required for Transformation J. Biol. Chem., December 24, 2004; 279(52): 54731 - 54741. [Abstract] [Full Text] [PDF]

				C. Pompeia, D. R. Hodge, C. Plass, Y.-Z. Wu, V. E. Marquez, J. A. Kelley, and W. L. Farrar Microarray Analysis of Epigenetic Silencing of Gene Expression in the KAS-6/1 Multiple Myeloma Cell Line Cancer Res., May 15, 2004; 64(10): 3465 - 3473. [Abstract] [Full Text] [PDF]

				D. A. Calderwood Integrin activation J. Cell Sci., March 1, 2004; 117(5): 657 - 666. [Abstract] [Full Text] [PDF]

				X. Liu, L. Charrier, A. Gewirtz, S. Sitaraman, and D. Merlin CD98 and Intracellular Adhesion Molecule I Regulate the Activity of Amino Acid Transporter LAT-2 in Polarized Intestinal Epithelia J. Biol. Chem., June 20, 2003; 278(26): 23672 - 23677. [Abstract] [Full Text] [PDF]

				B. K. Shin, H. Wang, A. M. Yim, F. Le Naour, F. Brichory, J. H. Jang, R. Zhao, E. Puravs, J. Tra, C. W. Michael, et al. Global Profiling of the Cell Surface Proteome of Cancer Cells Uncovers an Abundance of Proteins with Chaperone Function J. Biol. Chem., February 21, 2003; 278(9): 7607 - 7616. [Abstract] [Full Text] [PDF]