The integrin α6β1 modulation of PI3K and Cdc42 activities induces dynamic filopodium formation in human platelets

Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, 112, Taiwan.
Journal of Biomedical Science (Impact Factor: 2.76). 01/2006; 12(6):881-98. DOI: 10.1007/s11373-005-9021-2
Source: PubMed


Platelets are an ideal model for studying a rapid morphological change in response to various signal transduction systems. Morphological changes via the activation of integrin alphaIIbbeta3 in platelets have been investigated intensively. In contrast, activation via integrin alpha6beta1 is less well studied. Here, we provide the first biochemical evidence that integrins alpha6beta1 and alphaIIbbeta3 of platelets are associated with different membrane proteins. We also demonstrate that platelets activated by integrin alpha6beta1 show dynamic change by actively forming filopodia and never fully spreading over a period of more than an hour. In addition, platelets activated by integrin alpha6beta1 are different from those activated by integrin alphaIIbbeta3 in terms of cell-substrate contact and in their distribution pattern of actin, Arp2/3 and various phosphotyrosine proteins. The morphological appearance of platelets produced through integrin alpha6beta1 activation is highly dependent on PI3 kinase (PI3K) but less dependent on Src kinase. Suppression of PI3K activity in integrin alpha6beta1 activated platelets induces an increase in Cdc42 activity and more filopodium formation. However, both Cdc42 and PI3K activity are higher in platelets activated by integrin alpha6beta1 than in those activated by integrin alphaIIbbeta3. Taken together, this study demonstrates that the signals induced by integrin alpha6beta1 modulate at the level of PI3K and Cdc42 activity to allow platelets to actively form filopodia.

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Available from: Hsin-Hou Chang, Aug 07, 2015
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    • "Although platelets express at least five different integrins, most of our understanding on the contribution of PI3K is related to studies on the two major receptors: integrin a IIb b 3 and integrin a 2 b 1 . Indeed, to our knowledge the investigation of the possible involvement of PI3K in platelet activation induced by other integrin receptors is limited to the work of Chang and collaborators, who demonstrated the importance of PI3K for integrin a 6 b 1 -mediated filipodia formation (Chang et al., 2005). "
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    ABSTRACT: Blood platelets are anucleated circulating cells that play a critical role in hemostasis and are also implicated in arterial thrombosis, a major cause of death worldwide. The biological function of platelets strongly relies in their reactiveness to a variety of extracellular agonists that regulate their adhesion to extracellular matrix at the site of vascular injury and their ability to form rapidly growing cell aggregates. Among the membrane receptors expressed on the cell surface, integrins are crucial for both platelet activation, adhesion and aggregation. Integrin affinity for specific ligands is regulated by intracellular signaling pathways activated in stimulated platelets, and, once engaged, integrins themselves generate and propagate signals inside the cells to reinforce and consolidate platelet response and thrombus formation. Phosphatidylinositol 3-Kinases (PI3Ks) have emerged as crucial players in platelet activation, and they are directly implicated in the regulation of integrin function. This review will discuss the contribution of PI3Ks in platelet integrin signaling, focusing on the role of specific members of class I PI3Ks and their downstream effector Akt on both integrin inside-out and outside-in signaling. The contribution of the PI3K/Akt pathways stimulated by integrin engagement and platelet activation in thrombus formation and stabilization will also be discussed in order to highlight the possibility to target these enzymes in effective anti-thrombotic therapeutic strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Advances in Biological Regulation 06/2015; DOI:10.1016/j.jbior.2015.06.001
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    • "Magnesium and manganese and cobaltact as cofactors for this interaction.6 α6β1 signaling to the platelets via phosphoinositide 3 kinase induces morphologic changes in the platelets.7 "
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    ABSTRACT: Platelets play an important role in hemostasis, inflammation, host defense, tumor growth and metastasis. Platelets receptors are instrumental in platelet-platelet aggregation and interaction of platelets with leukocytes, endothelial cells and coagulation factors. These receptors are also the targets for antiplatelet drugs. This review focuses on the role of platelet receptors in human physiology. Data were extracted from peer-reviewed journals using MEDLINE and EMBASE databases, and the following terms (platelets, platelet receptors, CD markers, integrins, tetraspanins, transmembrane receptors, prostaglandin receptors, immunoglobulin superfamily receptors) were used.
    Pakistan Journal of Medical Sciences Online 04/2013; 29(3):891-896. DOI:10.12669/pjms.293.3497 · 0.23 Impact Factor
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    • "The actin rearrangements that underlie these shape change events are regulated by Rho-type (Ras-homology) G-proteins. These small GTPases have prominent roles in regulation of cell shape, polarity and motility and in platelets, are involved in formation of focal adhesions (RhoA) [3], lamellipodia (Rac) [4] and filopodia (Cdc42) [5], [6], [7]. "
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    ABSTRACT: Formation of filopodia and other shape change events are vital for platelet hemostatic function. The mechanisms regulating filopodia formation by platelets are incompletely understood however. In particular the small GTPase responsible for initiating filopodia formation by platelets remains elusive. The canonical pathway involving Cdc42 is not essential for filopodia formation in mouse platelets. The small GTPase Rif (RhoF) provides an alternative route to filopodia generation in other cell types and is expressed in both human and mouse platelets. We hypothesized that Rif might be responsible for generating filopodia by platelets and generated a novel knockout mouse model to investigate the functional role of Rif in platelets. Constitutive RhoF(-/-) mice are viable and have normal platelet, leukocyte and erythrocyte counts and indices. RhoF(-/-) platelets form filopodia and spread normally on various agonist surfaces in static conditions and under arterial shear. In addition, RhoF(-/-) platelets have normal actin dynamics, are able to activate and aggregate normally and secrete from alpha and dense granules in response to collagen related peptide and thrombin stimulation. The small GTPase Rif does not appear to be critical for platelet function in mice. Functional overlap between Rif and other small GTPases may be responsible for the non-essential role of Rif in platelets.
    PLoS ONE 01/2013; 8(1):e54663. DOI:10.1371/journal.pone.0054663 · 3.23 Impact Factor
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