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J. Biol. Chem., Vol. 280, Issue 23, 21756-21762, June 10, 2005

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The Pro³³ Isoform of Integrin ₃ Enhances Outside-in Signaling in Human Platelets by Regulating the Activation of Serine/Threonine Phosphatases^*

K. Vinod Vijayan, Yan Liu, Wensheng Sun, Masaaki Ito, and Paul F. Bray¶||

From the ^¶Department of Medicine, Baylor College of Medicine, Houston, Texas 77030 and the 1st Department of Internal Medicine, Mie University School of Medicine, Mie, 514-8507 Japan

Integrin ₃ is polymorphic at residue 33 (Leu³³ or Pro³³), and the Pro³³-positive platelets display enhanced aggregation, P-selectin secretion, and shorter bleeding times. Because outside-in signaling is critical for platelet function, we hypothesized that the Pro³³ variant provides a more efficient signaling than the Leu³³ isoform. When compared with Pro³³-negative platelets, Pro³³-positive platelets demonstrated significantly greater serine/threonine phosphorylation of extracellular signal-regulated kinase (ERK2) and myosin light chain (MLC) but not cytoplasmic phospholipase A2 upon thrombin-induced aggregation. Tyrosine phosphorylation of integrin ₃ and the adaptor protein Shc was no different in the fibrinogen-engaged platelets from both genotypes. The addition of Integrilin (_IIb3-fibrinogen blocker) or okadaic acid (serine/threonine phosphatase inhibitor) dramatically enhanced ERK2 and MLC phosphorylation in the Pro³³-negative platelets when compared with Pro³³-positive platelets, suggesting that integrin engagement during platelet aggregation activates serine/threonine phosphatases. The phosphatase activity of myosin phosphatase (MP) that dephosphorylates MLC is inactivated by phosphorylation of the myosin binding subunit of MP at Thr⁶⁹⁶, and aggregating Pro³³-positive platelets exhibited an increased Thr⁶⁹⁶ phosphorylation of MP. These studies highlight a role for the dephosphorylation events via the serine/threonine phosphatases during the integrin outside-in signaling mechanism, and the Leu³³ Pro polymorphism regulates this process. Furthermore, these findings support a mechanism whereby the reported enhanced granule secretion in the Pro³³-positive platelets could be mediated by an increased phosphorylation of MLC, which in turn is caused by an increased phosphorylation and subsequent inactivation of myosin phosphatase.

Received for publication, January 24, 2005 , and in revised form, March 1, 2005.

^* This work was supported in part by Grants HL57488 and HL65967 from the National Institute of Health and by a grant from the Fondren Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Scientist Development Grant 0435017N from the National American Heart Association. To whom correspondence may be addressed: Thrombosis Research Section, Baylor College of Medicine, One Baylor Plaza, BCM 286, N1319, Houston, TX 77030. Tel.: 713-798-3480; Fax: 713-798-3415; E-mail: vvijayan{at}bcm.tmc.edu. || To whom correspondence may be addressed: Thrombosis Research Section, Baylor College of Medicine, One Baylor Plaza, BCM 286, N1319, Houston, TX 77030. Tel.: 713-798-3480; Fax: 713-798-3415; E-mail: pbray{at}bcm.tmc.edu.

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