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SHIP2 is Recruited to the Cell Membrane via its Proline-Rich Domain upon M-CSF Stimulation and Regulates M-CSF-Induced Signaling

SHIP2 is Recruited to the Cell Membrane via its Proline-Rich Domain upon M-CSF Stimulation and Regulates M-CSF-Induced Signaling

FASEB Journal 18(4-5): Abst 337 20

Src homology 2-containing inositol 5&39;-phosphatase 2 (SHIP2) is believed to play an important role in negative regulation of insulin signaling. We reported here SHIP2 becomes tyrosine phosphorylated upon stimulation with Macrophage Colony-Stimulating Factor (M-CSF) in human alveolar macrophages, human monocytic THP-1 cells, murine bone marrow-derived macrophages and murine macrophage RAW264 cells. By using 3T3/fms as a model, we identified that SHIP2 co-immunoprecipitates with the M-CSF receptor and translocates to the membrane upon M-CSF stimulation. Next, we try to reveal the molecular mechanism of how SHIP2 functions to regulate M-CSF signaling. We found that localization to the cell membrane requires the proline-rich domain (PRD) of SHIP2 but is not dependent on its SH2 domain. Expressing either wild type SHIP2 or an SH2 domain mutant of SHIP2 reduced Akt activation in response to M-CSF-stimulation. In contrast, expression of a catalytically deficient mutant of SHIP2 or the proline-rich domain of SHIP2 enhances Akt activation to M-CSF stimulation. Furthermore, expression of wild type SHIP2 inhibits NFkB-mediated gene transcription in THP-1 cells. Here we present evidence for an additional and novel level of regulation of the M-CSF-R signaling by the inositol phosphatase SHIP2.Supported by RO-1 HL63800, HL67176, RO-1 HL66108, P01HL070294.

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