A newly identified complex of spinophilin and the tyrosine phosphatase, SHP-1, modulates platelet activation by regulating G protein-dependent signaling.
Platelets are essential for normal hemostasis, but close regulation is required to avoid the destructive effects of either inappropriate platelet activation or excessive responses to injury. Here, we describe a novel complex comprising the scaffold protein, spinophilin (SPL), and the tyrosine phosphatase, SHP-1, and show that it can modulate platelet activation by sequestering RGS10 and RGS18, 2 members of the regulator of G protein signaling family. We also show that SPL/RGS/SHP1 complexes are present in resting platelets where constitutive phosphorylation of SPL(Y398) creates an atypical binding site for SHP-1. Activation of the SHP-1 occurs on agonist-induced phosphorylation of SHP-1(Y536), triggering dephosphorylation and decay of the SPL/RGS/SHP1 complex. Preventing SHP-1 activation blocks decay of the complex and produces a gain of function. Conversely, deleting spinophilin in mice inhibits platelet activation. It also attenuates the rise in platelet cAMP normally caused by endothelial prostacyclin (PGI(2)). Thus, we propose that the role of the SPL/RGS/SHP1 complex in platelets is time and context dependent. Before injury, the complex helps maintain the quiescence of circulating platelets by maximizing the impact of PGI(2). After injury, the complex gradually releases RGS proteins, limiting platelet activation and providing a mechanism for temporal coordination of pro thrombotic and antithrombotic inputs.
Department of Medicine and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Peisong
P
Ma
Aleksandra
A
Cierniewska
Rachel
R
Signarvic
Marcin
M
Cieslak
Hong
H
Kong
Andrew J
AJ
Sinnamon
Richard R
RR
Neubig
Debra K
DK
Newman
Timothy J
TJ
Stalker
Lawrence F
LF
Brass
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015539:Platelet Activation; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D000099273:Neurabins
D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D020710:RGS Proteins; D014443:Tyrosine; D000099273:Neurabins; C101113:RGS10 protein, human; C466958:RGS18 protein, human