| First Author | Khatlani T | Year | 2023 |
| Journal | Cells | Volume | 12 |
| Issue | 20 | PubMed ID | 37887268 |
| Mgi Jnum | J:357931 | Mgi Id | MGI:7544290 |
| Doi | 10.3390/cells12202424 | Citation | Khatlani T, et al. (2023) Opposing Roles for the alpha Isoform of the Catalytic Subunit of Protein Phosphatase 1 in Inside-Out and Outside-In Integrin Signaling in Murine Platelets. Cells 12(20) |
| abstractText | Platelet activation during hemostasis and thrombosis is facilitated by agonist-induced inside-out and integrin alpha(IIb)beta(3)-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 PP1calpha(-/-) mice to explore the contribution of a major PP1 isoform in platelet functions. Loss of PP1calpha moderately decreased activation of integrin alpha(IIb)beta(3), binding of soluble fibrinogen, and aggregation to low-dose thrombin, ADP, and collagen. In contrast, PP1calpha(-/-) 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 PP1calpha(-/-) 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 PP1calpha(-/-) mice. Thus, PP1calpha displays pleiotropic signaling in platelets as it amplifies agonist-induced signaling and attenuates integrin-mediated signaling with no impact on hemostasis and thrombosis. |
