Fc Rgamma -independent signaling by the platelet collagen receptor glycoprotein VI.
The platelet collagen receptor glycoprotein VI (GPVI) is structurally homologous to multisubunit immune receptors and signals through the immune receptor adaptor Fc Rgamma. Multisubunit receptors are composed of specialized subunits thought to be dedicated exclusively to ligand binding or signal transduction. However, recent studies of the intracellular region of GPVI, a ligand-binding subunit, have suggested the existence of protein-protein interactions that could regulate receptor signaling. In the present study we have investigated the signaling role of the GPVI intracellular domain by stably expressing GPVI mutants in RBL-2H3 cells, a model system that accurately reproduces the GPVI signaling events observed in platelets. Studies of mutant GPVI receptor protein-protein interaction and calcium signaling reveal the existence of discrete domains within the receptor's intracellular tail that mediate interaction with Fc Rgamma, calmodulin, and Src family tyrosine kinases. These receptor interactions are modular and mediated by non-overlapping regions of the receptor transmembrane and intracellular domains. GPVI signaling requires all three of these domains as receptor mutants able to couple to only two interacting proteins exhibited severe signaling defects despite normal surface expression. Our results demonstrate that the ligand-binding subunit of the GPVI-Fc Rgamma receptor participates directly in receptor signaling by interacting with downstream signaling molecules other than Fc Rgamma through an adaptor-like mechanism.
Locke
Darren
D
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6100, USA.
Liu
Changdong
C
Peng
Xiaohui
X
Chen
Hong
H
Kahn
Mark L
ML
D000595:Amino Acid Sequence; D001665:Binding Sites; D002147:Calmodulin / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D002147:Calmodulin; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; C098341:platelet membrane glycoprotein VI; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases