Deficiency of Src homology 2 domain-containing inositol 5-phosphatase 1 affects platelet responses and thrombus growth.
Platelets are critical for normal hemostasis. Their deregulation can lead to bleeding or to arterial thrombosis, a primary cause of heart attack and ischemic stroke. Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) is a 5-phosphatase capable of dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate second messenger into phosphatidylinositol 3,4-bisphosphate. SHIP1 plays a critical role in regulating the level of these 2 lipids in platelets. Using SHIP1-deficient mice, we found that its loss affects platelet aggregation in response to several agonists with minor effects on fibrinogen binding and beta(3) integrin tyrosine phosphorylation. Accordingly, SHIP1-null mice showed defects in arterial thrombus formation in response to a localized laser-induced injury. Moreover, these mice had a prolonged tail bleeding time. Upon stimulation, SHIP1-deficient platelets showed large membrane extensions, abnormalities in the open canalicular system, and a dramatic decrease in close cell-cell contacts. Interestingly, SHIP1 appeared to be required for platelet contractility, thrombus organization, and fibrin clot retraction. These data indicate that SHIP1 is an important element of the platelet signaling machinery to support normal hemostasis. To our knowledge, this is the first report unraveling an important function of SHIP1 in the activation of hematopoietic cells, in contrast to its well-documented role in the negative regulation of lymphocytes.
Séverin
Sonia
S
INSERM U 563, Centre de Physiopathologie de Toulouse Purpan et Université Paul Sabatier, Département d' Oncogenèse et Signalisation dans les Cellules Hématopoïétiques, Toulouse, France.
Gratacap
Marie-Pierre
MP
Lenain
Nadège
N
Alvarez
Laetitia
L
Hollande
Etienne
E
Penninger
Josef M
JM
Gachet
Christian
C
Plantavid
Monique
M
Payrastre
Bernard
B
D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006487:Hemostasis / Q000235:genetics; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics; D017384:Sequence Deletion; D015398:Signal Transduction; D013927:Thrombosis / Q000235:genetics*; D018909:src Homology Domains / Q000235:genetics*
D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases