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Maintenance of murine platelet homeostasis by the kinase Csk and the phosphatase CD148

Jun Mori, Zoltan Nagy, Giada Di Nunzio, Christopher W. Smith, Mitchell J. Geer, Rashid Al Ghaithi, Johanna P. van Geffen, Silke Heising, Luke Boothman, Bibian M. E. Tullemans, Joao N. Correia, Louise Tee, Marijke J. E. Kuijpers, Paul Harrison, Johan W. M. Heemskerk, Gavin E. Jarvis, Alexander Tarakhovsky, Arthur Weiss, Alexandra Mazharian and Yotis A. Senis

Key points

  • Csk and CD148 are non-redundant regulators of SFKs in platelets and deletion of either induces cell-intrinsic negative feedback mechanisms

  • Csk is a negative regulator of SFK activity, whereas CD148 is a dual positive and negative regulator of SFK activity in platelets

Abstract

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.

  • Submitted February 9, 2017.
  • Accepted December 23, 2017.