Structural insights into the activation mechanism of the Janus kinase 2 mutant V617F
(2009)
Files
246993_Dusa_These.pdf
Restricted Access - Adobe PDF
- 8.95 MB
Details
- Authors
- Supervisors
- Constantinescu, Stefan
- Abstract
- Myeloproliferative neoplasms are clonal hematologic malignancies believed to develop following a transformation in a hematopoietic stem cell. In 2005 it was discovered that 90% of polycythemia vera patients and 50% of essential thrombocythemia and primary myelofibrosis patients harbor a unique point mutation at position 617 of JAK2, in the form of a Val to Phe substitution. The aim of this thesis was to elucidate the structural and molecular details of the activation mechanism of JAK2 V617F. We first established that in addition to Phe, four other large non-polar amino acids can induce constitutive activity of JAK2 when substituted for Val at position 617: Ile, Leu, Met and Trp. Out of them, only Trp induced a signal comparable in strength with Phe and triggered a myeloproliferative phenotype in mice. The three-nucleotide change needed to obtain the codon for Trp from Val (GTC to TGG) explains why only the V617F is prevalent in patients, since Phe can be obtained by mutating only one nucleotide (GTC to TTC). The homologous mutation in JAK1, V658W also induces constitutive activity of the kinase, pointing to a similar mechanism of activation. Given the constitutive activity of JAK2 V617I, V617M and V617L, in addition to V617F, we searched for possible contact points between JH1 and JH2 domains. We show that a specific residue in JH2 makes a key contact with F617, and that this contact is required for the constitutive activity of JAK2 V617F.
- Affiliations
Citations
Dusa, A. (2009). Structural insights into the activation mechanism of the Janus kinase 2 mutant V617F. https://hdl.handle.net/2078.5/111968