Phosphatidylinositol-3' kinase is not required for mitogenesis or internalization of the Flt3/Flk2 receptor tyrosine kinase.
Flt3/Flk2 is a receptor tyrosine kinase that is expressed on early hematopoietic progenitor cells. Flt3/Flk2 belongs to a family of receptors, including Kit and colony-stimulating factor-1R, which support growth and differentiation within the hematopoietic system. The Flt3/Flk2 ligand, in combination with other growth factors, stimulates the proliferation of hematopoietic progenitors of both lymphoid and myeloid lineages in vitro. We report that phosphatidylinositol 3'-kinase (PI3K) binds to a unique site in the carboxy tail of murine Flt3/Flk2. In distinction to Kit and colony-stimulating factor-1R, mutant receptors unable to couple to PI3K and expressed in rodent fibroblasts or in the interleukin 3-dependent cell line Ba/F3 provide a mitogenic signal comparable to wild-type receptors. Flt3/Flk2 receptors that do not bind to PI3K also normally down-regulate, a function ascribed to PI3K in the context of other receptor systems. These data point to the existence of other unidentified pathways that, alone or in combination with PI3K, transduce these cellular responses following the activation of Flt3/Flk2.
Beslu
N
N
Molecular Hematology Laboratory, Unite 119, Institut National de la Santé et de la Recherche Mèdicale, 27 Bd Lei Roure, 13009 Marseille, France.
LaRose
J
J
Casteran
N
N
Birnbaum
D
D
Lecocq
E
E
Dubreuil
P
P
Rottapel
R
R
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D008938:Mitosis; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D011506:Proteins; D011518:Proto-Oncogene Proteins; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3