A novel type I fibroblast growth factor receptor activates mitogenic signaling in the absence of detectable tyrosine phosphorylation of FRS2.
A novel variant of the fibroblast growth factor receptor type 1 (FGFR-1) was identified in human placental RNA. In this receptor (FGFR-1L) portions of the second and third immunoglobulin-like (Ig-like) domains are deleted. To determine whether FGFR-1L was functional, full-length variant (pSV/FGFR-1L) and wild-type (pSV/FGFR-1) receptors were stably transfected into ... rat L6 myoblasts cells. Transfected L6 clones expressed respective proteins and bound (125)I-labeled FGF-2 with K(d) values of 99 pm (FGFR-1) and 26 pm (FGFR-1L). FGF-1 and FGF-2 competed efficiently with (125)I-FGF-2 for binding to FGFR-1 and FGFR-1L, whereas FGF-4 was less efficient. FGF-1, FGF-2, and FGF-4 enhanced mitogen-activated protein kinase (MAPK) activity, increased steady-state c-fos mRNA levels, and stimulated proliferation through either receptor, whereas KGF was without effect. FGFR-1 expressing clones exhibited ligand-induced tyrosine phosphorylation of fibroblast growth factor receptor substrate 2 (FRS2), a 90-kDa adaptor protein that links FGFR-1 activation to the MAPK cascade. In contrast, tyrosine phosphorylation of FRS2 was not evident with FGFR-1L. In addition, phospholipase C-gamma was not tyrosine phosphorylated via activated FGFR-1L. These findings indicate that FGFR-1L binds FGF-1 and FGF-2 with high affinity and is capable of mitogenic signaling, but may activate MAPK to occur via non-classical signaling intermediates.
Mesh Terms:
Amino Acid Sequence, Animals, Base Sequence, Cell Division, Cell Line, Cloning, Molecular, Fibroblast Growth Factors, Humans, Isoenzymes, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Phospholipase C gamma, Phosphorylation, Placenta, Protein Binding, Proto-Oncogene Proteins c-fos, RNA, Messenger, Rats, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Fibroblast Growth Factor, Sequence Alignment, Signal Transduction, Transfection, Type C Phospholipases
Amino Acid Sequence, Animals, Base Sequence, Cell Division, Cell Line, Cloning, Molecular, Fibroblast Growth Factors, Humans, Isoenzymes, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Phospholipase C gamma, Phosphorylation, Placenta, Protein Binding, Proto-Oncogene Proteins c-fos, RNA, Messenger, Rats, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Fibroblast Growth Factor, Sequence Alignment, Signal Transduction, Transfection, Type C Phospholipases
J. Biol. Chem.
Date: May. 26, 2000
PubMed ID: 10748122
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