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PMID: 11865067 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Activated Fes protein tyrosine kinase induces terminal macrophage differentiation of myeloid progenitors (U937 cells) and activation of the transcription factor PU.1.

Molecular and cellular biology ·Vol. 22 ·No. 6 ·2002-03-00 ·Pages 1903-18

Kim J, Feldman RA

Abstract

The c-fps/fes proto-oncogene encodes a 92-kDa protein tyrosine kinase that is preferentially expressed in myeloid and endothelial cells. Fes is believed to play a role in vascular development and myelopoiesis and in the inflammatory responses of granulocytes and macrophages. To help define the biological role of this kinase and identify its downstream targets, we have developed a gain-of-function allele of Fes that has potent biological activity in myeloid cell progenitors. Introduction of constitutively active Fes into bipotential U937 cells induced the appearance of fully differentiated macrophages within 6 to 12 days. The Fes-expressing differentiated cells became adherent, had distinctive macrophage morphology, and exhibited increased expression of myelomonocytic differentiation markers, including CD11b, CD11c, CD18, CD14, and the macrophage colony-stimulating factor receptor. These cells acquired phagocytic properties and exhibited NADPH oxidase and nonspecific esterase activities, confirming that they were functionally active macrophages. Concomitantly, there was downregulation of the granulocytic marker granulocyte colony-stimulating factor receptor, indicating that the biological activity of Fes was coordinated in a lineage-specific manner. A constitutively active Src did not induce macrophage morphology or upregulation of myelomonocytic markers in U937 cells, suggesting that the biological activity we observed was not a general consequence of expression of an activated nonreceptor tyrosine kinase. Analysis of possible downstream targets of Fes revealed that this kinase activated the ets family transcription factor PU.1, which is essential for macrophage development. Our results strongly implicate Fes as a key regulator of terminal macrophage differentiation and identify PU.1 as a transcription factor that may mediate some of its biological activities in myeloid cells.

MeSH Terms
Alleles Antigens, CD/biosynthesis Antigens, Differentiation/biosynthesis Cell Differentiation/drug effects Cytoplasm/metabolism Enzyme Activation/physiology Fusion Proteins, gag-onc/genetics,metabolism,pharmacology Humans Macrophages/cytology,drug effects Myeloid Progenitor Cells/cytology,drug effects,metabolism Phenotype Protein-Tyrosine Kinases/genetics,metabolism,pharmacology Proto-Oncogene Mas Proto-Oncogene Proteins/metabolism Receptor, Macrophage Colony-Stimulating Factor/biosynthesis Recombinant Fusion Proteins/genetics,metabolism,pharmacology Signal Transduction/physiology Thromboplastin/metabolism Trans-Activators/metabolism Transfection U937 Cells
Chemicals
Antigens, CD Antigens, Differentiation Fusion Proteins, gag-onc MAS1 protein, human Proto-Oncogene Mas Proto-Oncogene Proteins Recombinant Fusion Proteins Trans-Activators proto-oncogene protein Spi-1 Thromboplastin Protein-Tyrosine Kinases Receptor, Macrophage Colony-Stimulating Factor v-fps oncogene protein, Fujinami sarcoma virus
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kim Jynho
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Feldman Ricardo A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.6.1903-1918.2002
Published
2002-03-00
Pages
1903-18
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC135606
Subset
IM
Grants
NCI NIH HHS · R01 CA055293 · United States
NCI NIH HHS · CA 55293 · United States
External Links
PubMed source DOI: 10.1128/MCB.22.6.1903-1918.2002 PMC Full Text View journal details
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