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.
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.
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Research Institute, OH 44195, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jiao
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Berrada
authors.forename: M
authors.initials: M
authors.lastname: Tabrizi
authors.forename: L
authors.initials: L
authors.lastname: Shultz
authors.forename: T
authors.initials: T
authors.lastname: Yi
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008894:Milk Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases