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Direct Rap1/Talin1 interaction regulates platelet and neutrophil integrin activity in mice

Thomas Bromberger, Sarah Klapproth, Ina Rohwedder, Liang Zhu, Laura Mittmann, Christoph A. Reichel, Markus Sperandio, Jun Qin and Markus Moser

Key points

  • Direct Rap1/Talin1 interaction controls platelet and neutrophil integrin functions.

  • Rap1/Talin1 interaction is important in blood cells, which depend on rapid integrin-mediated processes.

Abstract

Targeting Talin1 to the plasma membrane is a crucial step in integrin activation, which in leukocytes is mediated by a Rap1/RIAM/Talin1 pathway whereas in platelets is RIAM-independent. Recent structural, biochemical and cell biological studies suggested a direct Rap1/Talin1 interaction as an alternative mechanism to recruit Talin1 to the membrane and induce integrin activation. To test whether this pathway is of relevance in vivo, we generated Rap1-binding-deficient Talin1 knockin (Tln13mut) mice. Although Tln13mut mice show no obvious abnormalities, their platelets exhibit reduced integrin activation, aggregation, adhesion and spreading resulting in prolonged tail-bleeding times and delayed thrombus formation and vessel occlusion in vivo. Surprisingly, neutrophil adhesion to different integrin ligands and β2 integrin-dependent phagocytosis are also significantly impaired, which causes a profound leukocyte adhesion and extravasation defect in Tln13mut mice. In contrast, macrophages exhibit no defect in adhesion and spreading despite reduced integrin activation. Taken together, our findings suggest that the direct Rap1/Talin1 interaction is of particular importance in regulating the activity of different integrin classes expressed on platelets and neutrophils, which both depend on very fast and dynamic integrin-mediated responses.

  • Submitted April 23, 2018.
  • Accepted November 8, 2018.