ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation

Proceedings of the National Academy of Sciences of the United States of America - Tập 112 Số 15 - Trang 4642-4647 - 2015
Henrik M. Hammarén1, Daniela Ungureanu1, Jean Grisouard2, Radek C. Skoda2, Stevan R. Hubbard3,4, Olli Silvennoinen5,1
1aSchool of Medicine, University of Tampere, FI-33014 Tampere, Finland;
2bDepartment of Biomedicine, Experimental Hematology, University Hospital Basel, CH-4031 Basel, Switzerland;
3Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016; and
4dDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016; and
5Clinical Hematology, Department of Internal Medicine, Tampere University Hospital, FI-33520 Tampere, Finland

Tóm tắt

SignificanceMutations in the JAK pseudokinase domain are bona fide oncogenic drivers that underlie many myeloproliferative and autoimmune diseases in humans. TheJAK2V617F mutation is responsible for ∼95% of polycythemia vera and ∼60% of primary myelofibrosis and essential thrombocytosis cases. Currently, developed JAK2 tyrosine kinase inhibitors have not been able to eradicate disease caused by mutated JAK2. The data presented here show that alteration of the ATP binding site of the pseudokinase domain has the potential to suppress JAK hyperactivation caused by pathogenic mutations, with minimal effects on wild-type JAK, thus establishing the ATP binding site of the pseudokinase domain as a potential pharmacological target.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 112 Số 15

4642-4647

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