Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role.
The immune receptor signaling pathway is used by nonimmune cells, but the molecular adaptations that underlie its functional diversification are not known. Circulating platelets use the immune receptor homologue glycoprotein VI (GPVI) to respond to collagen exposed at sites of vessel injury. In contrast to immune cell responses, platelet activation must take place within seconds to successfully form thrombi in flowing blood. Here, we show that the GPVI receptor utilizes a unique intracellular proline-rich domain (PRD) to accelerate platelet activation, a requirement for efficient platelet adhesion to collagen under flow. The GPVI PRD specifically binds the Src-family kinase Lyn and directly activates it, presumably through SH3 displacement. In resting platelets, Lyn is constitutively bound to GPVI in an activated state and platelets lacking Lyn exhibit defective collagen adhesion like that of platelets with GPVI receptors lacking the PRD. These findings define a molecular priming mechanism that enables an immune-type receptor to adopt a hemostatic function. These studies also demonstrate that active kinases can constitutively associate with immune-type receptors without initiating signal transduction before receptor ligation, consistent with a recent molecular model of immune receptor signaling in which receptor ligation is required to bring active kinases to their receptor substrates.
Schmaier
Alec A
AA
Department of Medicine, Division of Cardiology, Division of Hematology, Institute for Medicine and Engineering, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Zou
Zhiying
Z
Kazlauskas
Arunas
A
Emert-Sedlak
Lori
L
Fong
Karen P
KP
Neeves
Keith B
KB
Maloney
Sean F
SF
Diamond
Scott L
SL
Kunapuli
Satya P
SP
Ware
Jerry
J
Brass
Lawrence F
LF
Smithgall
Thomas E
TE
Saksela
Kalle
K
Kahn
Mark L
ML
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D006487:Hemostasis; D051379:Mice; D015539:Platelet Activation / Q000276:immunology; D010973:Platelet Adhesiveness; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D011392:Proline; D019061:src-Family Kinases / Q000378:metabolism*
D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen; D011392:Proline; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases