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A newly identified complex of spinophilin and the tyrosine phosphatase, SHP-1, modulates platelet activation by regulating G protein-dependent signaling. Blood 2012 Feb 23;119(8):1935-45

Date

01/03/2012

Pubmed ID

22210881

Pubmed Central ID

PMC3293648

DOI

10.1182/blood-2011-10-387910

Scopus ID

2-s2.0-84857520121 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

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.

Author List

Ma P, Cierniewska A, Signarvic R, Cieslak M, Kong H, Sinnamon AJ, Neubig RR, Newman DK, Stalker TJ, Brass LF

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Binding Sites
Blood Platelets
Blotting, Western
CHO Cells
Cricetinae
Cricetulus
Cyclic AMP
GTP-Binding Proteins
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Microfilament Proteins
Models, Biological
Mutation
Nerve Tissue Proteins
Phosphorylation
Platelet Activation
Protein Binding
Protein Tyrosine Phosphatase, Non-Receptor Type 6
RGS Proteins
Signal Transduction
Transfection
Tyrosine