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Constitutively activated FLT3 phosphorylates BAD partially through Pim‐1
Author(s) -
Kim KyuTae,
Levis Mark,
Small Donald
Publication year - 2006
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2006.06225.x
Subject(s) - mapk/erk pathway , protein kinase b , kinase , microbiology and biotechnology , phosphorylation , fms like tyrosine kinase 3 , cancer research , map kinase kinase kinase , biology , signal transduction , receptor tyrosine kinase , biochemistry , mutation , gene
Summary Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms‐like tyrosine kinase 3) play an important role in leukaemogenesis and their presence is associated with a poor prognosis in acute myeloid leukaemia (AML). Examining the anti‐ and pro‐apoptotic proteins in constitutively activated FLT3 signalling in BaF3/ITD and MV4‐11 cells, we found that the level of Bcl‐2 antagonist of cell death (BAD) phosphorylation was greatly decreased in response to FLT3 inhibition. Both Ser‐112 and Ser‐136 of BAD are rapidly dephosphorylated after treatment with the FLT3 inhibitor CEP‐701 in BaF3/ITD and MV4‐11 cells. In confirmation of the cell line data, BAD was highly phosphorylated in both constitutively activated wild‐type and mutant FLT3 primary AML samples, and rapidly dephosphorylated after treatment of the primary samples with CEP‐701. Upstream proteins known to phosphorylate BAD include Akt, extracellular signal‐regulated kinase/mitogen‐activated protein kinase (Erk/MAPK), Pim‐1 and Pim‐2. We and other groups have shown that constitutively activated FLT3 induces multiple signalling pathways, including phosphatidylinositol 3‐kinase (PI3K)/Akt, Erk/MAPK and Janus kinase/signal transducers and activators of transcription (Jak/STAT). Thus, BAD may be a nexus point upon which these multiple signalling pathways converge in FLT3‐mediated cell survival. In support of this, siRNA knockdown of BAD expression in MV4‐11 cells conferred resistance to CEP‐701‐mediated apoptosis. Our data suggests that Pim‐1 is one of the principal kinases mediating the anti‐apoptotic function of FLT3/ITD signalling via the phosphorylation of BAD.