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TC 21/ RR as2 regulates glycoprotein VI –FcRγ‐mediated platelet activation and thrombus stability
Author(s) -
Janapati S.,
Wurtzel J.,
Dangelmaier C.,
Manne B. K.,
Bhavanasi D.,
Kostyak J. C.,
Kim S.,
Holinstat M.,
Kunapuli S. P.,
Goldfinger L. E.
Publication year - 2018
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14197
Subject(s) - gpvi , microbiology and biotechnology , platelet , platelet activation , integrin , platelet membrane glycoprotein , chemistry , syk , signal transduction , proto oncogene tyrosine protein kinase src , cortactin , tyrosine phosphorylation , biology , receptor , tyrosine kinase , biochemistry , cytoskeleton , immunology , cell
Essentials RAS proteins are expressed in platelets but their functions are largely uncharacterized. TC21/RRas2 is required for glycoprotein VI‐induced platelet responses and for thrombus stability in vivo . TC21 regulates platelet aggregation by control of α IIb β 3 integrin activation, via crosstalk with Rap1b. This is the first indication of functional importance of a proto‐oncogenic RAS protein in platelets.Summary Background Many RAS family small GTP ases are expressed in platelets, including RAC , RHOA , RAP , and HRAS / NRAS / RRAS 1, but most of their signaling and cellular functions remain poorly understood. Like RRAS 1, TC 21/ RRAS 2 reverses HRAS ‐induced suppression of integrin activation in CHO cells. However, a role for TC 21 in platelets has not been explored. Objectives To determine TC 21 expression in platelets, TC 21 activation in response to platelet agonists, and roles of TC 21 in platelet function in in vitro and in vivo thrombosis. Results We demonstrate that TC 21 is expressed in human and murine platelets, and is activated in response to agonists for the glycoprotein ( GP ) VI –FcRγ immunoreceptor tyrosine‐based activation motif ( ITAM )‐containing collagen receptor, in an Src‐dependent manner. GPVI ‐induced platelet aggregation, integrin α II b β 3 activation, and α‐granule and dense granule secretion, as well as phosphorylation of Syk, phospholipase Cγ2, AKT , and extracellular signal‐regulated kinase, were inhibited in TC 21‐deficient platelets ex vivo . In contrast, these responses were normal in TC 21‐deficient platelets following stimulation with P2Y, protease‐activated receptor 4 and C‐type lectin receptor 2 receptor agonists, indicating that the function of TC 21 in platelets is GPVI –FcRγ‐ ITAM ‐specific. TC 21 was required for GPVI ‐induced activation of Rap1b. TC 21‐deficient mice did not show a significant delay in injury‐induced thrombosis as compared with wild‐type controls; however, thrombi were unstable. Hemostatic responses showed similar effects. Conclusions TC 21 is essential for GPVI –FcRγ‐mediated platelet activation and for thrombus stability in vivo via control of Rap1b and integrins.