Distinct and overlapping functional roles of Src family kinases in mouse platelets

Séverin, Sonia; Nash, Craig; Mori, Jun; Zhao, Yan; Abram, Clare L.; Lowell, Clifford A.; Senis, Yotis A.; Watson, Steve P.

doi:10.1111/j.1538-7836.2012.04814.x

Cited by 47 publications

(66 citation statements)

References 63 publications

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“…This may affect the positive regulatory activity of FCRL4 on CpG stimulation in the context of FGR or HCK p59 expression, or on BCR signaling in the context of HCK p59 expression because the increase in the observed reporter gene activity was dependent on expression of a palmitoylation-proficient FCRL4. Palmitoylation of FCRL4 may therefore facilitate the colocalization of FCRL4 with FGR and HCK p59 src-family kinases, which are subject to the same posttranslational modification and are found in detergent insoluble fractions (49)(50)(51). In support of this possibility, it is noteworthy that we observed regulatory activity of FCRL4 in the context of FGR or HCK p59, but not HCK p61.…”

Section: Discussionsupporting

confidence: 72%

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Liu

Bezverbnaya

Zhao

et al. 2015

The Journal of Immunology

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FCRL4 is an immunoregulatory receptor expressed by a subpopulation of memory B cells. These tissue-based cells express increased levels of the src-family kinases HCK and FGR. In this study, we investigate the roles of these src-family kinases in FCRL4-mediated immunoregulation of B cells in the context of previously unrecognized palmitoylation of the receptor. We observed enhanced phosphorylation of FCRL4 on tyrosine residues in the presence of the HCK p59 or FGR. This phosphorylation was markedly reduced in assays using a palmitoylation-defective mutant of FCRL4. In reporter gene studies, we observe that FCRL4 expression enhances CpG-mediated activation of NF-κB signaling. Surprisingly, using a reporter gene linked to activation of the MAPK substrate Elk-1 in response to Ag receptor ligation, we find that FCRL4 has inhibitory activity in cells coexpressing FGR but an activating function in cells coexpressing HCK p59. We provide evidence that in primary memory B cells, expression of FCRL4 leads to increased expression of IL-10 in the presence of FGR or HCK p59 in response to CpG, but increased levels of IFN-γ only in the context of coexpression of FGR. Our study supports the specific requirement of HCK p59 and FGR src-family kinases for FCRL4-mediated immunomodulatory activity and indicates that palmitoylation serves as an additional level of regulatory control of FCRL4.

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Section: Discussionsupporting

confidence: 72%

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Liu

Bezverbnaya

Zhao

et al. 2015

The Journal of Immunology

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“…17,18 In hemostasis and thrombosis, GPVI supports platelet adhesion and aggregation. GPVI is critical for the maintenance of vessel wall integrity in inflammation 19 by inhibiting neutrophil-induced vascular damage.…”

Section: Introductionmentioning

confidence: 99%

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Montague

Delierneux

Lecut³

et al. 2018

Blood Advances

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• Soluble GPVI is elevated in patients with thermal injury with sepsis, and sGPVI levels augment severity score prediction of mortality.• The GPVI ligand, fibrin, induces GPVI shedding without requirement for platelet activation or signaling Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU)for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28-and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 59-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

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“…15 Seven SFKs (Src, Yes, Lyn, Hck, Fyn, Fgr, and Lck) have been reported in human platelets and four (Src, Lyn, Fyn, and Fgr) have been reported in mouse platelets (Table 1). [16][17][18][19][20][21] A number of structurally distinct broad-spectrum SFK inhibitors (PP1, PP2, SU6656, PD0173952) and knockout mouse models have been used to elucidate the contributions of these SFKs to platelet signal transduction and function. The most well-established functions are summarized in Table 1.…”

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confidence: 99%

“…Fgr and Yes are expressed at much lower levels than Src, Lyn, and Fyn in platelets and have been implicated in ITAM-containing and integrin receptor signaling, respectively. 21,25 Below, we discuss our current understanding of how Src, Lyn, and Fyn work in conjunction to regulate an optimal level of platelet activation.…”

mentioning

confidence: 99%

“…47 Mouse platelets lacking Src exhibit severely impaired tyrosine phosphorylation and spreading on fibrinogen. 21,31 Similarly, disruption of the Src-b3 interaction, either by deleting or mutating the b3 RGT sequence reduces outside-in signaling and platelet spreading on fibrinogen and clot retraction, which culminates in reduced thrombus formation and a mild bleeding diathesis. 48 However, defects are not as severe as those seen in the presence of SFK inhibitors, 31,49 suggesting that there is functional redundancy between SFKs.…”

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confidence: 99%

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Src family kinases: at the forefront of platelet activation

Senis

Mazharian

Mori

2014

Blood

247

214

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Src family kinases (SFKs) play a central role in mediating the rapid response of platelets to vascular injury. They transmit activation signals from a diverse repertoire of platelet surface receptors, including the integrin αIIbβ3, the immunoreceptor tyrosine–based activation motif–containing collagen receptor complex GPVI-FcR γ-chain, and the von Willebrand factor receptor complex GPIb-IX-V, which are essential for thrombus growth and stability. Ligand-mediated clustering of these receptors triggers an increase in SFK activity and downstream tyrosine phosphorylation of enzymes, adaptors, and cytoskeletal proteins that collectively propagate the signal and coordinate platelet activation. A growing body of evidence has established that SFKs also contribute to Gq- and Gi-coupled receptor signaling that synergizes with primary activation signals to maximally activate platelets and render them prothrombotic. Interestingly, SFKs concomitantly activate inhibitory pathways that limit platelet activation and thrombus size. In this review, we discuss past discoveries that laid the foundation for this fundamental area of platelet signal transduction, recent progress in our understanding of the distinct and overlapping functions of SFKs in platelets, and new avenues of research into mechanisms of SFK regulation. We also highlight the thrombotic and hemostatic consequences of targeting platelet SFKs.

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Distinct and overlapping functional roles of Src family kinases in mouse platelets

Cited by 47 publications

References 63 publications

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Src family kinases: at the forefront of platelet activation

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