WASP plays a novel role in regulating platelet responses dependent on αIIbβ3 integrin outside-in signalling
Anna Shcherbina
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Research Institute for Paediatric Haematology, Moscow, Russia
Search for more papers by this authorJessica Cooley
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorMaxim I. Lutskiy
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorCharaf Benarafa
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorGary E. Gilbert
Department of Medicine, VA Boston Healthcare System, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA
Search for more papers by this authorEileen Remold-O’Donnell
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorAnna Shcherbina
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Research Institute for Paediatric Haematology, Moscow, Russia
Search for more papers by this authorJessica Cooley
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorMaxim I. Lutskiy
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorCharaf Benarafa
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorGary E. Gilbert
Department of Medicine, VA Boston Healthcare System, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA
Search for more papers by this authorEileen Remold-O’Donnell
Immune Disease Institute, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorSummary
The most consistent feature of Wiskott Aldrich syndrome (WAS) is profound thrombocytopenia with small platelets. The responsible gene encodes WAS protein (WASP), which functions in leucocytes as an actin filament nucleating agent –yet– actin filament nucleation proceeds normally in patient platelets regarding shape change, filopodia and lamellipodia generation. Because WASP localizes in the platelet membrane skeleton and is mobilized by αIIbβ3 integrin outside-in signalling, we questioned whether its function might be linked to integrin. Agonist-induced αIIbβ3 activation (PAC-1 binding) was normal for patient platelets, indicating normal integrin inside-out signalling. Inside-out signalling (fibrinogen, JON/A binding) was also normal for wasp-deficient murine platelets. However, adherence/spreading on immobilized fibrinogen was decreased for patient platelets and wasp-deficient murine platelets, indicating decreased integrin outside-in responses. Another integrin outside-in dependent response, fibrin clot retraction, involving contraction of the post-aggregation actin cytoskeleton, was also decreased for patient platelets and wasp-deficient murine platelets. Rebleeding from tail cuts was more frequent for wasp-deficient mice, suggesting decreased stabilisation of the primary platelet plug. In contrast, phosphatidylserine exposure, a pro-coagulant response, was enhanced for WASP-deficient patient and murine platelets. The collective results reveal a novel function for WASP in regulating pro-aggregatory and pro-coagulant responses downstream of integrin outside-in signalling.
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