期刊
BLOOD
卷 136, 期 10, 页码 1180-1190出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005348
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资金
- Chao Family Comprehensive Cancer Center Support Grant from the National Institutes of Health, National Cancer Institute [P30CA062203]
- European Union's Horizon 2020 Research and Innovation Program [841428]
- American Heart Association Career Development Award [18CDA34110228, 17POST33660181, 16GRNT29650005]
- National Institutes of Health, National Heart, Lung and Blood Institute [KO1 HL133530, HL078784, HL139947, R35 HL144976]
- Marie Curie Actions (MSCA) [841428] Funding Source: Marie Curie Actions (MSCA)
Ras-related protein 1 (Rap1) is a major convergence point of the platelet-signaling pathways that result in talin-1 binding to the integrin beta cytoplasmic domain and consequent integrin activation, platelet aggregation, and effective hemostasis. The nature of the connection between Rap1 and talin-1 in integrin activation is an important remaining gap in our understanding of this process. Previous work identified a low-affinity Rap1-binding site in the talin-1 F0 domain that makes a small contribution to integrin activation in platelets. We recently identified an additional Rap1-binding site in the talin-1 F1 domain that makes a greater contribution than F0 in model systems. Here we generated mice bearing point mutations, which block Rap1 binding without affecting talin-1 expression, in either the talin-1 F1 domain (R118E) alone, which were viable, or in both the F0 and F1 domains (R35E,R118E), which were embryonic lethal. Loss of the Rap1-talin-1 F1 interaction in platelets markedly decreases talin-1-mediated activation of platelet beta 1- and beta 3-integrins. Integrin activation and platelet aggregation in mice whose platelets express only talin1(R35E, R118E) are even more impaired, resembling the defect seen in platelets lacking both Rap1a and Rap1b. Although Rap1 is important in thrombopoiesis, platelet secretion, and surface exposure of phosphatidylserine, loss of the Rap1-talin-1 interaction in talin-1(R35E, R118E) platelets had little effect on these processes. These findings show that talin-1 is the principal direct effector of Rap1 GTPases that regulates platelet integrin activation in hemostasis.
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