Distinct Pathways Regulate Syk Protein Activation Downstream of Immune Tyrosine Activation Motif (ITAM) and hemITAM Receptors in Platelets

Manne, Bhanu Kanth; Badolia, Rachit; Dangelmaier, Carol; Eble, Johannes A.; Ellmeier, Wilfried; Kahn, Mark L.; Kunapuli, Satya P.

doi:10.1074/jbc.m114.629527

Cited by 65 publications

(72 citation statements)

References 74 publications

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“…In platelets, Syk was found to associate with the actin filament cross-linking protein filamin A, thereby relocalizing Syk to the plasma membrane and rendering it susceptible to activation through tyrosine kinases (95). In a more recent study with CLEC-2, it was shown that Syk activation depends on the Src-PI3K-Tec pathway (96). Although it was concluded that Tec family kinases (TFKs) phosphorylate Syk in a CLEC-2-bound state, the requirement for a CLEC-2-Syk association was not shown (96).…”

Section: Syk Activation Without Recruitment By a Hemitammentioning

confidence: 99%

“…In a more recent study with CLEC-2, it was shown that Syk activation depends on the Src-PI3K-Tec pathway (96). Although it was concluded that Tec family kinases (TFKs) phosphorylate Syk in a CLEC-2-bound state, the requirement for a CLEC-2-Syk association was not shown (96). Hence, this Syk activation pathway may possibly represent a mechanism of Syk activation that is independent of Syk recruitment to a hemITAM.…”

Section: Syk Activation Without Recruitment By a Hemitammentioning

confidence: 99%

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HemITAM: A single tyrosine motif that packs a punch

Bauer

Steinle

2017

Sci. Signal.

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Section: Syk Activation Without Recruitment By a Hemitammentioning

confidence: 99%

Section: Syk Activation Without Recruitment By a Hemitammentioning

confidence: 99%

HemITAM: A single tyrosine motif that packs a punch

Bauer

Steinle

2017

Sci. Signal.

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“…Activation of platelets by binding of CLEC‐2 to its ligand podoplanin on lymphatic vessel endothelial cells has been found to be a major mechanism for maintaining blood‐lymphatic separation 83. Inhibition of TFKs in murine platelets with ibrutinib abolishes aggregation responses to CLEC‐2 stimulation completely, and embryos of BTK/TEC KO mice exhibit cutaneous oedema with blood‐filled vessels with a lymphatic pattern similar to CLEC‐2‐deficient mice 82. Furthermore, engagement of the fibrinogen receptor integrin α IIb β 3 has been reported to induce BTK and TEC phosphorylation 84, 85, indicating that the kinases are not only involved in the initial activation of platelets at sites where the extracellular matrix is exposed to the blood stream, but also in later stages of thrombus formation.…”

Section: Consequences Of Ibrutinib Treatment Not Related To B Cellsmentioning

confidence: 99%

Targets for Ibrutinib Beyond B Cell Malignancies

et al. 2015

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Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.

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“…In platelets, BTK acts within the signalosome downstream of several receptors, including the collagen receptor GPVI and the podoplanin receptor CLEC-2, 4 where it promotes phospholipase (PL) Cγ phosphorylation. Several labs have shown that ibrutinib can impair platelet activation in vitro, 4,5 and platelets taken from ibrutinibtreated patients have an impaired response to collagen and reduced adhesion to von Willebrand Factor (vWF) ex vivo.…”

mentioning

confidence: 99%

“…Several labs have shown that ibrutinib can impair platelet activation in vitro, 4,5 and platelets taken from ibrutinibtreated patients have an impaired response to collagen and reduced adhesion to von Willebrand Factor (vWF) ex vivo. 6,7 It has therefore been suggested that ibrutinibinduced platelet dysfunction underlies bleeding in patients.…”

mentioning

confidence: 99%