Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F.
The JAK2 mutation JAK2V617F is found frequently in patients with myeloproliferative disorders (MPD) and transforms hematopoietic cells to cytokine-independent proliferation when expressed with specific cytokine receptors. The Src homology 2 (SH2) and pleckstrin homology (PH) domain-containing adaptor protein Lnk (SH2B3) is a negative regulator of hematopoietic cytokine signaling. Here, we show that Lnk is a potent inhibitor of JAK2V617F constitutive activity. Lnk down-regulates JAK2V617F-mediated signaling and transformation in hematopoietic Ba/F3-erythropoietin receptor cells. Furthermore, in CFU assays, Lnk-deficient murine bone marrow cells are significantly more sensitive to transformation by JAK2V617F than wild-type (WT) cells. Lnk, through its SH2 and PH domains, interacts with WT and mutant JAK2 and is phosphorylated by constitutively activated JAK2V617F. Finally, we found that Lnk levels are high in CD34(+) hematopoietic progenitors from MPD patients and that Lnk expression is induced following JAK2 activation. Our data suggest that JAK2V617F is susceptible to endogenous negative-feedback regulation, providing new insights into the molecular pathogenesis of MPD.
Gery
Sigal
S
Davis Bldg. 5066, 8700 Beverly Blvd., Los Angeles, CA 90048, USA. gerys@cshs.org
Cao
Qi
Q
Gueller
Saskia
S
Xing
Hongtao
H
Tefferi
Ayalew
A
Koeffler
H Phillip
HP
D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D004789:Enzyme Activation; D006413:Hematopoietic System / Q000166:cytology / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D050505:Mutant Proteins / Q000037:antagonists & inhibitors*; D022423:Myeloid Cells / Q000166:cytology / Q000201:enzymology; D009196:Myeloproliferative Disorders / Q000201:enzymology*; D010649:Phenylalanine / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D014633:Valine / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D050505:Mutant Proteins; D011506:Proteins; C490778:SH2B3 protein, human; D010649:Phenylalanine; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D014633:Valine