Maintenance of murine platelet homeostasis by the kinase Csk and 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, Yotis A. Senis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, but 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 glycoprotein VI (GPVI)-Fc receptor (FcR) gamma-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 analog-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.
Original languageEnglish
Pages (from-to)1122-1144
Number of pages23
JournalBlood
Volume131
Issue number10
DOIs
Publication statusPublished - 8 Mar 2018

Keywords

  • SRC FAMILY KINASES
  • PROTEIN-TYROSINE-PHOSPHATASE
  • RECEPTOR-GAMMA-CHAIN
  • ADHESION MOLECULE-1 PECAM-1
  • BETA CYTOPLASMIC DOMAIN
  • VON-WILLEBRAND-FACTOR
  • TANDEM SH2 DOMAINS
  • T-LINEAGE CELLS
  • IN-VIVO
  • GLYCOPROTEIN-VI

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