Dissociation of SHP-1 from spinophilin during platelet activation exposes an inhibitory binding site for protein phosphatase-1 (PP1)

We have recently shown that a critical regulatory node in the platelet signaling network lies immediately downstream of platelet receptors for thrombin and TxA2. This node is comprised of a scaffold protein (spinophilin, SPL), a protein tyrosine phosphatase (SHP-1), and either of the two members of...

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Bibliographic Details
Published in:PloS one 2015-03, Vol.10 (3), p.e0119496-e0119496
Main Authors: Ma, Peisong, Foote, Darci C, Sinnamon, Andrew J, Brass, Lawrence F
Format: Article
Language:English
Subjects:
Adenosine diphosphate
Animals
Binding Sites
Biochemistry
Blood platelets
Blood Platelets - metabolism
Blood Platelets - physiology
Cell culture
Cell cycle
Chemical properties
CHO Cells
Collagen
Cricetulus
Dissociation
G proteins
Humans
Isoforms
Kinases
Light
Medicine
Microfilament Proteins - blood
Muscle proteins
Myosin
Nerve Tissue Proteins - blood
Overexpression
Pharmacology
Phosphatase
Phosphatases
Phosphoprotein phosphatase
Phosphorylation
Platelet Activation - physiology
Platelets
Protein binding
Protein phosphatase
Protein Tyrosine Phosphatase, Non-Receptor Type 6 - blood
Protein-serine/threonine phosphatase
Protein-tyrosine-phosphatase
Proteins
Receptors
Receptors, Neuropeptide Y - blood
Regulators
RGS Proteins - blood
Serine
SHP-1 protein
Signaling
Spinophilin
Substrates
Threonine
Threonine phosphatase
Thrombin
Thrombin - metabolism
Tyrosine
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Summary:We have recently shown that a critical regulatory node in the platelet signaling network lies immediately downstream of platelet receptors for thrombin and TxA2. This node is comprised of a scaffold protein (spinophilin, SPL), a protein tyrosine phosphatase (SHP-1), and either of the two members of the Regulators of G protein Signaling family predominantly expressed in platelets (RGS10 or RGS18). The SPL/RGS/SHP-1 complex is present in resting platelets, dissociating when thrombin or TxA2, but not ADP or collagen, activate SHP-1 and release RGS10 and RGS18 to dampen signaling. Here we demonstrate an additional regulatory role for spinophilin, showing that dissociation of SHP-1 from spinophilin is followed by an increase in the binding of spinophilin to PP1, a serine/threonine phosphatase whose binding site maps to a region close to the SHP-1 binding site. The increase in PP1 binding to spinophilin is limited to platelet agonists that cause dissociation of the complex and is selective for the α and γ isoforms of PP1. Studies in cell culture show that SHP-1 and PP1 can compete for binding to spinophilin and that binding inhibits PP1 activity since over-expression of wild type spinophilin, but not spinophilin with a disabled PP1 binding site, causes an increase in the phosphorylation of myosin light chain, a well-characterized PP1 substrate. Collectively, these results indicate that in addition to regulating RGS protein availability in resting platelets, spinophilin can serve as a time-dependent, agonist- and isoform-selective regulator of PP1, inhibiting its activity when decay of the SPL/RGS/SHP-1 complex releases SHP-1 from spinophilin, exposing a binding site for PP1.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0119496