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) 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 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.

中文翻译：

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通过激酶 Csk 和磷酸酶 CD148 维持鼠血小板稳态

Src 家族激酶 (SFK) 协调血小板中的启动和传播激活信号，但尚不清楚它们是如何调节的。在这里，我们表明在小鼠中消融 C 端 Src 激酶 (Csk) 和受体样蛋白酪氨酸磷酸酶 CD148 导致血小板 SFK 活性显着增加，表明这些蛋白质是血小板反应性的重要调节剂。矛盾的是，Csk/CD148 缺陷小鼠表现出体内和体外血栓形成减少和损伤后出血增加，而不是促血栓形成表型。这是多种负反馈机制的结果，包括下调基于免疫受体酪氨酸的激活基序 (ITAM) 和含半 ITAM 的受体糖蛋白 VI (GPVI)-Fc 受体 (FcR) γ-链和 CLEC-2，分别上调基于免疫受体酪氨酸的抑制基序 (ITIM) 的受体 G6b-B 及其与酪氨酸磷酸酶 Shp1 和 Shp2 的相互作用。模拟敏感 Csk 小鼠模型的结果证明了 SFK 在激活 ITIM 信号中的非常规作用。该研究将 Csk 和 CD148 确定为控制血小板血栓形成和止血能力的关键分子开关，并揭示了防止病理性血栓形成发生的细胞内在机制。