TC21/RRas2 regulates glycoprotein VI–FcRγ‐mediated platelet activation and thrombus stability
Author(s): ,
S. Janapati
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
,
J. Wurtzel
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Anatomy & Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
,
C. Dangelmaier
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
,
B. K. Manne
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
,
D. Bhavanasi
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
,
J. C. Kostyak
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
,
S. Kim
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
,
M. Holinstat
Affiliations:
Department of Pharmacology, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, USA
,
S. P. Kunapuli
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
L. E. Goldfinger
Affiliations:
The Sol Sherry Thrombosis Research Center and Department of Anatomy & Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA. College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
Correspondence: Lawrence Goldfinger, Department of Anatomy and Cell Biology and the Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, 3420 N. Broad Street, Philadelphia, PA, USA|Tel.: +1215 707 8157|E‐mail: goldf
ISTH Academy. Goldfinger L. Aug 2, 2018; 227431
Lawrence Goldfinger
Lawrence  Goldfinger

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Background
Many RAS family small GTPases are expressed in platelets, including RAC, RHOA, RAP, and HRAS/NRAS/RRAS1, but most of their signaling and cellular functions remain poorly understood. Like RRAS1, TC21/RRAS2 reverses HRAS‐induced suppression of integrin activation in CHO cells. However, a role for TC21 in platelets has not been explored.
Objectives
To determine TC21 expression in platelets, TC21 activation in response to platelet agonists, and roles of TC21 in platelet function in in vitro and in vivo thrombosis.
Results
We demonstrate that TC21 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 αβ 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 TC21‐deficient platelets ex vivo. In contrast, these responses were normal in TC21‐deficient platelets following stimulation with P2Y, protease‐activated receptor 4 and C‐type lectin receptor 2 receptor agonists, indicating that the function of TC21 in platelets is GPVI–FcRγ‐ITAM‐specific. TC21 was required for GPVI‐induced activation of Rap1b. TC21‐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
TC21 is essential for GPVI–FcRγ‐mediated platelet activation and for thrombus stability in vivo via control of Rap1b and integrins.
Keyword(s)
blood platelets, collagen receptors, embolism and thrombosis, monomeric GTP‐binding proteins, RAS proteins
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