CD98-dependent homotypic aggregation is associated with translocation of protein kinase Cdelta and activation of mitogen-activated protein kinases.
CD98 is a protein found on the surface of many activated cell types, and is implicated in the regulation of cellular differentiation, adhesion, growth, and apoptosis. Despite many studies addressing CD98 function, there is little information on the intracellular signalling pathways that mediate its activity. In this study, we examine protein kinase pathways that are activated following ligation by the CD98 antibody AHN-18, an antibody that induces U937 homotypic aggregation and inhibits antigen presenting activity and T-cell activation. Ligation by CD98 antibody AHN-18 induces tyrosine kinase activity, but inhibition of this activity does not affect U937 aggregation. Ligation also induces membrane translocation of the serine/threonine kinase novel PKCdelta, but not other members of the PKC family. Translocation is blocked by rottlerin, and this inhibitor also blocks aggregation. PKCdelta activation in turn mediates activation of ERK1/2 and p38, as well as tyrosine phosphorylation of multiple proteins, and MAPK activation is essential for cellular aggregation. One of the targets of CD98-induced tyrosine phosphorylation is itself PKCdelta, suggesting that this phosphorylation may act as a negative feedback to limit the overall activation of the CD98 pathway.
Department of Immunology and Molecular Pathology, Windeyer Institute of Medical Sciences, University College London, 46 Cleveland Street, London W1T 6JF, UK.
Jae Youl
JY
Cho
Keith M
KM
Skubitz
David R
DR
Katz
Benjamin M
BM
Chain
D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000906:Antibodies / Q000378:metabolism; D002449:Cell Aggregation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D027261:Fusion Regulatory Protein-1 / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011433:Propranolol / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D021381:Protein Transport; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D000906:Antibodies; D004791:Enzyme Inhibitors; D027261:Fusion Regulatory Protein-1; D014443:Tyrosine; D011433:Propranolol; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases