Tyrosine 201 is required for constitutive activation of JAK2V617F and efficient induction of myeloproliferative disease in mice.
Blood
; 120(9): 1888-98, 2012 Aug 30.
Article
em En
| MEDLINE
| ID: mdl-22837531
ABSTRACT
The JAK2V617F mutation has been detected in most cases of Ph-negative myeloproliferative neoplasms (MPNs). The JAK2V617F protein is a constitutively activated tyrosine kinase that leads to transformation of hematopoietic progenitors. Previous studies have shown that several tyrosine residues within JAK2 are phosphorylated on growth factor or cytokine stimulation. However, the role of these tyrosine residues in signaling and transformation mediated by JAK2V617F remains unclear. In this study, we sought to determine the role of tyrosine 201, which is a potential binding site for Src homology 2 domain-containing proteins, in JAK2V617F-induced hematopoietic transformation by introducing a tyrosine-to-phenylalanine point mutation (Y201F) at this site. We observed that the Y201F mutation significantly inhibited cytokine-independent cell growth and induced apoptosis in Ba/F3-EpoR cells expressing JAK2V617F. The Y201F mutation also resulted in significant inhibition of JAK2V617F-mediated transformation of hematopoietic cells. Biochemical analyzes revealed that the Y201F mutation almost completely inhibited constitutive phosphorylation/activation of JAK2V617F. We also show that the Y201 site of JAK2V617F promotes interaction with Stat5 and Shp2, and constitutive activation of downstream signaling pathways. Furthermore, using a BM transduction/transplantation approach, we found that tyrosine 201 plays an important role in the induction of MPNs mediated by JAK2V617F.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tirosina
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Mutação de Sentido Incorreto
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Janus Quinase 2
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Transtornos Mieloproliferativos
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos