Src tyrosine kinase preactivation is associated with platelet hypersensitivity in essential thrombocythemia and polycythemia vera.
Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders characterized by an increased incidence of thrombo-hemorrhagic complications. The acquired somatic Janus kinase 2 (JAK2) V617F mutation is present in the majority of PV and ET patients. Because aberrant protein Tyr-phosphorylation has been associated with hematopoietic malignancies, the activity of the tyrosine kinases Src and JAK2 was analyzed in resting and thrombin-stimulated platelets from 13 PV and 42 ET patients. JAK2 was found inactive in healthy and pathological resting cells regardless of the V617F mutation. In addition, Src was inactive in all resting platelets, but in the pathological specimens it was present in a preactivated conformation as a consequence of anomalous dephosphorylation of its inhibitory phospho-Tyr527 residue, likely mediated by Src homology-2 domain-containing protein Tyr-phosphatase-2 (SHP-2), whose constitutive activity correlated with its recruitment to Src. Low thrombin concentration triggered a more rapid Src-signaling activation, higher [Ca(2+)](c) increase, and aggregation in pathological platelets compared with controls. Thrombin-induced Src activation preceded JAK2 activation, which occurred simultaneously in normal and pathological platelets. Our results indicate that a constitutive Src kinase preactivation is implicated in platelet hypersensitivity and likely involved, at least partially, in the functional abnormalities of PV and ET platelets.
Randi
Maria Luigia
ML
Department of Medical and Surgical Sciences, University of Padova, Padova, Italy.
Brunati
Anna Maria
AM
Scapin
Margherita
M
Frasson
Martina
M
Deana
Renzo
R
Magrin
Elisa
E
Fabris
Fabrizio
F
Donella-Deana
Arianna
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D015539:Platelet Activation / Q000502:physiology; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013917:Thrombin / Q000378:metabolism / Q000502:physiology; D013920:Thrombocythemia, Essential / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism*
C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019061:src-Family Kinases; D013917:Thrombin