Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148
Research output: Contribution to journal › Article
Colleges, School and Institutes
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Netherlands.
- University of Cambridge
- Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY, United States.
- Howard Hughes Medical Institute, University of California, San Francisco, United States.
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham
Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, however it remains unclear how they are regulated. Here we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury, rather than a prothrombotic phenotype. This is a consequence of multiple negative feedback mechanisms, including downregulation of the immunoreceptor tyrosine-based activation motif (ITAM)- and hemi-ITAM-containing receptors GPVI-FcR γ-chain and CLEC-2, respectively and upregulation of the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B and its interaction with the tyrosine phosphatases Shp1 and Shp2. Results from an analogue-sensitive Csk mouse model demonstrate the unconventional role of SFKs in activating ITIM signaling. This study establishes Csk and CD148 as critical molecular switches controlling the thrombotic and hemostatic capacity of platelets, and reveals cell-intrinsic mechanisms that prevent pathological thrombosis from occurring.
|Early online date||4 Jan 2018|
|Publication status||Published - 8 Mar 2018|
- Journal Article