TY - JOUR
T1 - Cell- and receptor isotype-specific phosphorylation of SNT1 by fibroblast growth factor receptor tyrosine kinases
AU - Wang, Fen
N1 - Funding Information:
I thank Dr. W. L. McKeehan for valuable discussion and criticism of the manuscript, and Kerstin McKeehan and Trinh Nguyen fiJr excellent technical assistance. This work was supported in part by NIH Grants DK35310 and CA59971 and a gift from the John S. Dunn Foundation.
PY - 2002
Y1 - 2002
N2 - A partnership between the ectodomain of the fibroblast growth factor receptor (FGFR) isotypes and the chains of pericellular matrix heparan sulfate determines the fibroblast growth factor (FGF) and cell-type specificitives of the FGFR signaling complex. The contribution of the FGFR intracellular tyrosine kinase domains to the specificity of FGFR signaling is unclear. This report shows that the quantity and quality of phosphorylation of the FGFR kinase substrate SNT1 (also called FGFR substrate 2, FRS2) is both FGFR isotype and cell-type specific in prostate tumor epithelial cells at different stages of malignancy. Epithelial cell-resident FGFR2 that promotes homeostasis yields a low level of phosphorylated 65-kDa SNT1. Phosphorylation by ectopic FGFR1 that promotes malignancy was much more intense and yielded a phosphorylated 85-kDa SNT1. The amount of the 85-kDa SNT1 increased by 20-fold during proliferative aging of FGFR1-expressing cell populations that is required for FGFRI-stimulated mitogenesis and the malignant phenotype. In addition, the receptor-specific differential phosphorylation of SNT1 by FGFR isotypes, both of which are normally anchored to the cell membrane, occurred only in intact cells. Therefore, similar to kinase subunits within the heparan sulfate-FGFR complex, cell membrane and cytoskeletal context likely determine FGFR isotype- and cell- type-specific conformational relationships between FGFR kinases and external substrates. This determines the quantity and quality of SNT1 phosphorylation and differential signaling.
AB - A partnership between the ectodomain of the fibroblast growth factor receptor (FGFR) isotypes and the chains of pericellular matrix heparan sulfate determines the fibroblast growth factor (FGF) and cell-type specificitives of the FGFR signaling complex. The contribution of the FGFR intracellular tyrosine kinase domains to the specificity of FGFR signaling is unclear. This report shows that the quantity and quality of phosphorylation of the FGFR kinase substrate SNT1 (also called FGFR substrate 2, FRS2) is both FGFR isotype and cell-type specific in prostate tumor epithelial cells at different stages of malignancy. Epithelial cell-resident FGFR2 that promotes homeostasis yields a low level of phosphorylated 65-kDa SNT1. Phosphorylation by ectopic FGFR1 that promotes malignancy was much more intense and yielded a phosphorylated 85-kDa SNT1. The amount of the 85-kDa SNT1 increased by 20-fold during proliferative aging of FGFR1-expressing cell populations that is required for FGFRI-stimulated mitogenesis and the malignant phenotype. In addition, the receptor-specific differential phosphorylation of SNT1 by FGFR isotypes, both of which are normally anchored to the cell membrane, occurred only in intact cells. Therefore, similar to kinase subunits within the heparan sulfate-FGFR complex, cell membrane and cytoskeletal context likely determine FGFR isotype- and cell- type-specific conformational relationships between FGFR kinases and external substrates. This determines the quantity and quality of SNT1 phosphorylation and differential signaling.
KW - FGFR specificity
KW - FRS2
KW - Prostate cancer
KW - Signal transduction
KW - Tumor progression
KW - Tyrosine phosphorylation
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U2 - 10.1290/1071-2690(2002)038<0178:CARISP>2.0.CO;2
DO - 10.1290/1071-2690(2002)038<0178:CARISP>2.0.CO;2
M3 - Article
C2 - 12026167
AN - SCOPUS:0036244318
SN - 1071-2690
VL - 38
SP - 178
EP - 183
JO - In Vitro Cellular and Developmental Biology - Animal
JF - In Vitro Cellular and Developmental Biology - Animal
IS - 3
ER -