CD98hc (SLC3A2) interaction with beta 1 integrins is required for transformation.
CD98hc (SLC3A2) constitutively and specifically associates with beta(1) integrins and is highly expressed on the surface of human tumor cells irrespective of the tissue of origin. We have found here that expression of CD98hc promotes both anchorage- and serum-independent growth. This oncogenic activity is dependent on beta(1) integrin-mediated phosphoinositol 3-hydroxykinase stimulation and the level of surface expression of CD98hc. Using chimeras of CD98hc and the type II membrane protein CD69, we show that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/beta(1) integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumor promotion by integrins. These results explain how high expression of CD98hc in human cancers contributes to transformation; furthermore, the transmembrane association of CD98hc and beta(1) integrins may provide a new target for cancer therapy.
Lung Inflammation Group, Medical Research Council Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh EH8 9XD, Scotland, UK.
Neil C
NC
Henderson
Elizabeth A
EA
Collis
Alison C
AC
Mackinnon
Kenneth J
KJ
Simpson
Christopher
C
Haslett
Roy
R
Zent
Mark
M
Ginsberg
Tariq
T
Sethi
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D016466:CHO Cells; D002455:Cell Division; D002462:Cell Membrane / Q000737:chemistry; D002471:Cell Transformation, Neoplastic; D006224:Cricetinae; D004347:Drug Interactions; D005455:Fluorescent Antibody Technique; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D019012:Integrin beta1 / Q000032:analysis / Q000502:physiology*; D037181:Lectins, C-Type; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D027282:Fusion Regulatory Protein 1, Heavy Chain; D019012:Integrin beta1; D037181:Lectins, C-Type; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D011993:Recombinant Fusion Proteins; D000099192:CD69 Antigens