Antithrombotic effects of targeting αIIbβ3 signaling in platelets

Ablooglu, Ararat J.; Kang, Jian; Petrich, Brian G.; Ginsberg, Mark H.; Shattil, Sanford J.

doi:10.1182/blood-2008-09-180687

Cited by 53 publications

(64 citation statements)

References 51 publications

(93 reference statements)

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“…Studies in human platelets (2,27) and in mouse models (28,29) have revealed an essential role for Src and/or Src-␣ IIb ␤ 3 interaction in outside-in ␣ IIb ␤ 3 integrin signaling dependent functions like adhesion, and spreading on fibrinogen. We observed that PP2Ac␣-depleted cells exhibited Src activation and increased adhesion to fibrinogen.…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between Serine/Threonine Protein Phosphatase 2A and Protein Tyrosine Phosphatase 1B Regulates Src Activation and Adhesion of Integrin αIIbβ3 to Fibrinogen

Pradhan

Alrehani

Patel

et al. 2010

Journal of Biological Chemistry

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Stable platelet-platelet and platelet-extracellular matrix interactions play a critical role in hemostasis and thrombosis. These interactions can be mediated by integrin ␣ IIb ␤ 3 signaling at the sites of vascular injury. The binding of ␣ IIb ␤ 3 to an extracellular ligand-like fibrinogen triggers outside-in signals in platelets via modulation of the activities of several kinases and phosphatases. These signals in turn regulate the cytoskeletal reorganization, which contributes to stable platelet adhesion and spreading events (1). Signaling molecules, including the tyrosine kinase c-Src (2), protein tyrosine phosphatase 1 B (PTP-1B) 3 (3), and the catalytic subunit of protein phosphatase 2A (PP2Ac) (4) either associate constitutively or are recruited to the ␣ IIb ␤ 3 complex in response to integrin engagement. Kinases and phosphatases that assemble within the protein complexes organized by the cytoplasmic tails of ␣ IIb and ␤ 3 could facilitate reversible phosphorylation of multiple effector proteins and mediate outside-in signaling process.Protein phosphatase 2A (PP2A) is a serine/threonine (Ser/ Thr) phosphatase that regulate cell growth, development, and apoptosis. PP2A holoenzyme contains the catalytic subunit C (PP2Ac) and the structural or scaffolding subunit A (PP2Aa). The A subunit of PP2A interacts with multiple regulatory B subunits and regulates the subcellular localization, substrate specificity, and the catalytic activity of PP2A (5). Although, PP2Ac exhibit ␣ and ␤ isoforms, a 10-fold abundant expression of PP2Ac␣ in most cell types (6) had led us to consider PP2Ac␣ in our previous integrin studies (4). These studies revealed that the depletion of PP2Ac␣ in 293 ␣ IIb ␤ 3 cells resulted in an enhanced adhesion to immobilized fibrinogen (4). However, an underlying mechanism is incompletely understood.Alternative model systems like 293 ␣ IIb ␤ 3 cells or Chinese Hamster Ovary (CHO) ␣ IIb ␤ 3 cells have proved useful in elucidating the signaling properties of integrin ␣ IIb ␤ 3 (7-9). In particular, such models are appealing if the role of the signaling molecules under study will be deciphered using a genetic approach. In the context of this study, embryonic lethality of PP2Ac␣-null mice (10), lack of a specific PP2Ac␣ pharmacological inhibitor, and the non feasibility of gene expression in anucleate platelets have limited the extensive use of platelets. The aim of this study in 293 ␣ IIb ␤ 3 cells was to elucidate the molecular events that underpin the PP2Ac␣ mediated negative regulation of ␣ IIb ␤ 3 cell adhesion. In particular; we wished to examine the regulation of c-Src activity (referred to as Src in this manuscript) by PP2Ac␣. c-Src signaling constitutes one of the early signaling events in the outside-in ␣ IIb ␤ 3 signaling process (11).In this study, we identified that loss of PP2Ac␣ activated Src via PTP-1B. Furthermore, Src and PTP-1B activity was required for the enhanced adhesive phenotype displayed by the PP2Ac␣-depleted 293 ␣ IIb ␤ 3 cells. * This work was supported, in whole or in part...

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Section: Discussionmentioning

confidence: 99%

Cross-talk between Serine/Threonine Protein Phosphatase 2A and Protein Tyrosine Phosphatase 1B Regulates Src Activation and Adhesion of Integrin αIIbβ3 to Fibrinogen

Pradhan

Alrehani

Patel

et al. 2010

Journal of Biological Chemistry

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“…19 Furthermore, it was shown that the C-terminal end of integrin ␤3 with the sequence R 760 GT 762 mediates a direct interaction with the SH3 domain of c-Src. 20,24,25 Contrary to the canonical SH3 domain ligands with a typical poly-Pro type II helix, 11,26,27 the integrin binding motif is much shorter and does not contain a proline residue. Recently, an in vitro study using synthetic peptides corresponding to the cytoplasmic tail of integrin showed that the sequence motif RGT can selectively inhibit outside-in signaling in human platelets.…”

Section: Introductionmentioning

confidence: 94%

“…24 This together with the in vivo study using knock-in mouse suggested that peptidomimetics derived from the RGT moiety might be promising thrombosis drug candidates with little side effect toward the normal function of platelet. 25 Furthermore, the complex of c-Src:␤3 was also reported as an "oncogenic unit" promoting tumor growth and metastasis. 28,29 Hence, these observations have led to the proposal and expectation that the interaction of c-Src:␤3 could serve as an interesting therapeutic target, and better understanding of this interaction might lead to the discovery of new antithrombotic and anticancer strategies.…”

Section: Introductionmentioning

confidence: 99%

Structural framework of c-Src activation by integrin β3

Xiao

Zhu

et al. 2013

Blood

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“…Although many current therapeutic strategies are aimed at blocking integrin association with ligands, there is a recent appreciation that an alternative strategy may be to target intracellular signalling mechanisms to inhibit integrin activation, thereby suppressing ligand binding, or to prevent the downstream sequela of integrin activation 116,[163][164][165] . Potential strategies are focused on the short cytoplasmic tails of the integrin α and β subunits, although there is also evidence that the transmembrane domains may play a role [103][104]166 .…”

Section: Receptor Antagonists That Do Not Induce Conformational Changmentioning

confidence: 99%