Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 84, Issue 3, Pages 852-863Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.0308171
Keywords
tyrosine kinase; tyrosine phosphorylation; hematopoietic growth factor; receptor tyrosine kinase mutations
Categories
Funding
- National Institutes of Health [CA26504, PO1 CA 100324, KO8 CA097348]
- Albert Einstein College of Medicine Cancer Center [5P30-CA13330]
- American Society of Hematology Fellow Scholar Award
- Leukemia and Lymphoma Society Special Fellow Award
- NATIONAL CANCER INSTITUTE [R37CA026504, R01CA026504, P01CA100324, K08CA097348] Funding Source: NIH RePORTER
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CSF- 1 is the major regulator of tissue macrophage development and function. A GMCSFdependent, CSF- 1 receptor (CSF- 1R)- deficient F4/ 80hiMac-1(+)Gr1(-)CD11c(+) bone marrow macrophage ( BMM) line (MacCsf1r -/ -) was developed to study the roles of the eight intracellular CSF- 1R tyrosines phosphorylated upon receptor activation. Retroviral expression of the wild- type CSF- 1R rescued the CSF- 1- induced survival, proliferation, differentiation, and morphological characteristics of primary BMM. Mutation of all eight tyrosines failed to rescue, whereas the individual Y 3 F mutants ( 544, 559, 697, 706, 721, 807, 921, 974) rescued these CSF- 1- inducible phenotypes to varying degrees. The juxtamembrane domain Y559F and activation loop Y807F mutations severely compromised proliferation and differentiation, whereas Y706, Y721F, and Y974F mutations altered morphological responses, and Y706F increased differentiation. Despite their retention of significant in vitro tyrosine kinase activity, Y559F and Y807F mutants exhibited severely impaired in vivo receptor tyrosine phosphorylation, consistent with the existence of cellular mechanisms inhibiting CSF- 1R tyrosine phosphorylation that are relieved by phosphorylation of these two sites. The MacCsf1r-/- macrophage line will facilitate genetic and proteomic approaches to CSF- 1R structure/ function studies in the major diseaserelated CSF- 1R- expressing cell type.
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