Opposing Roles for the α Isoform of the Catalytic Subunit of Protein Phosphatase 1 in Inside-Out and Outside-In Integrin Signaling in Murine Platelets

Authors

Tanvir Khatlani
Subhashree Pradhan
Kimberly Langlois
Deepika Subramanyam
Rolando E Rumbaut
K Vinod Vijayan

Publication Date

10-10-2023

Journal

Cells

DOI

10.3390/cells12202424

PMID

37887268

PMCID

PMC10605409

PubMedCentral® Posted Date

10-10-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Animals, Protein Phosphatase 1, Catalytic Domain, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Isoforms, Thrombosis, Collagen, Fibrinogen, platelets, protein phosphatase 1 alpha, p38 mitogen-activated protein kinase, fibrinogen

Abstract

Platelet activation during hemostasis and thrombosis is facilitated by agonist-induced inside–out and integrin αIIbβ3-initiated outside–in signaling via protein kinases and phosphatases. Pharmacological inhibitor studies suggest that the serine/threonine protein phosphatase 1 (PP1) promotes platelet activation. However, since phosphatase inhibitors block all the isoforms of the catalytic subunit of PP1 (PP1c), the role of specific PP1c isoform in platelet signaling remains unclear. Here, we employed a platelet-specific PP1cα−/− mice to explore the contribution of a major PP1 isoform in platelet functions. Loss of PP1cα moderately decreased activation of integrin αIIbβ3, binding of soluble fibrinogen, and aggregation to low-dose thrombin, ADP, and collagen. In contrast, PP1cα−/− platelets displayed increased adhesion to immobilized fibrinogen, fibrin clot retraction, and thrombus formation on immobilized collagen. Mechanistically, post-fibrinogen engagement potentiated p38 mitogen-activated protein kinase (MAPK) activation in PP1cα−/− platelets and the p38 inhibitor blocked the increased integrin-mediated outside–in signaling function. Tail bleeding time and light-dye injury-induced microvascular thrombosis in the cremaster venules and arterioles were not altered in PP1cα−/− mice. Thus, PP1cα displays pleiotropic signaling in platelets as it amplifies agonist-induced signaling and attenuates integrin-mediated signaling with no impact on hemostasis and thrombosis.

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