SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor

• Published in: Leukemia Vol. 13; no. 9; pp. 1374 - 1382
• Main Authors: MARCHETTO, S, FOURNIER, E, BESLU, N, AURRAN-SCHLEINITZ, T, DUBREUIL, P, BORG, J.-P, BIRNBAUM, D, ROSNET, O
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.09.1999; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Binding; Biological and medical sciences; Cancer immunotherapy; Cell differentiation, maturation, development, hematopoiesis; Cell growth; Cell Line; Cell physiology; Cell proliferation; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Genes, myc; Genetic Code; Hematopoietic stem cells; Homology; Immunotherapy; Inositol; Inositols; Intracellular signalling; Kinases; Kinetics; Molecular and cellular biology; myo-Inositol-1 (or 4)-monophosphatase; Natural killer cells; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Phosphotyrosine; Progenitor cells; Protein-tyrosine kinase receptors; Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptors; Retroviridae - genetics; Shc protein; Shc Signaling Adaptor Proteins; Ships; src Homology Domains; Stem cells; Tyrosine; Human; Cell proliferation; Cell culture; Signal transduction; Phosphorylation; Regulation(control); Enzyme; Hematopoiesis; Transferases; In vitro; Protein-tyrosine kinase; Biological receptor
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2401527

The FLT3 receptor tyrosine kinase and its ligand, FL, regulate the development of hematopoietic stem cells and early B lymphoid progenitors. FL has a strong capacity to boost production of dendritic and natural killer cells in vivo, thereby providing a new and promising tool for anti-cancer immunotherapy. Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SHC possesses two phosphotyrosine-binding domains: an amino-terminal phosphotyrosine binding (PTB) and a carboxy-terminal Src Homology 2 (SH2) domain. Neither is required for SHC phosphorylation, but the PTB domain is necessary and sufficient for SHC binding to the SH2 containing inositol phosphatase (SHIP). Overexpression of SHC increases the level of SHIP phosphorylation on tyrosines in response to FLT3 activation, suggesting that SHC availability is a limiting step for SHIP phosphorylation. This effect is observed only if the SHC PTB domain is functional. Interestingly, SHC overexpression in FLT3-activatable Ba/F3 cells limits FLT3-dependent cell growth and this effect requires tyrosine 313. Taken together, the present data show that SHC can antagonize cell proliferation induced by FLT3 stimulation and regulate phosphorylation of the SHIP negative regulator. In addition, our study provides the structural bases for SHC phosphorylation and formation of the SHC/SHIP complex.