Faculty Research 1990 - 1999

Title

Macrophages from motheaten and viable motheaten mutant mice show increased proliferative responses to GM-CSF: detection of potential HCP substrates in GM-CSF signal transduction.

Document Type

Article

Publication Date

1997

Keywords

Animal, Bone-Marrow: cy, Calmodulin-Dependent-Protein-Kinases: me, Cell-Division, Cells-Cultured, DNA-Binding-Proteins: me, Granulocyte-Macrophage-Colony-Stimulating-Factor, Hematopoiesis, Macrophage-Colony-Stimulating-Factor, Macrophages: cy, Mice, Mice-Inbred-C57BL, Mice-Mutant-Strains, Phosphoproteins: me, Phosphorylation, Protein-Binding, Protein-Tyrosine-Kinase: me, Protein-Tyrosine-Phosphatase: me, Receptors-Granulocyte-Macrophage-Colony-Stimulating-Factor, Signal-Transduction, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Trans-Activators: me

JAX Source

Exp Hematol 1997 Jul;25(7):592-600

Grant

CA20408/CA/NCI

Abstract

Loss of functional hematopoietic cell phosphatase (HCP) underlies severe hematopoietic and immunologic abnormalities in mice homozygous for the motheaten and viable motheaten mutations. These mice die from pulmonary accumulation of macrophages that are regulated by macrophage colony-stimulating factor (M-CSF) and granulocyte (G)-M-CSF. We determined the growth response of motheaten macrophages to the two growth factors and looked for potential HCP substrates in these cells. Motheaten macrophages showed increased proliferative responses to GM-CSF but not to M-CSF, demonstrating that HCP plays a critical role in downregulating GM-CSF mitogenic signaling. Despite the heightened growth responses of the motheaten macrophages to GM-CSF, there were no marked differences between motheaten macrophages and normal controls in GM-CSF-induced phosphorylation of GM-CSFR beta, Jak2, STAT5 and MAPK, indicating that these molecules are not major HCP substrates in GM-CSF signaling. Interestingly, several markedly hyperphosphorylated proteins were detected in the motheaten macrophages, including a novel 126-kDa phosphotyrosine protein that associated with the phosphatase via its SH2 domains, suggesting that these proteins depend on HCP for dephosphorylation and may mediate the heightened growth responses to GM-CSF. Our data indicate that macrophage hypersensitivity to GM-CSF may be a major factor in motheaten pathogenesis and that HCP may dephosphorylate novel substrates critical in GM-CSF mitogenic signaling.

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