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.
Lopez
M E
ME
Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine, Biological Chemistry, and Pharmacology, University of California, Irvine, California 92697, USA.
Korc
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D003001:Cloning, Molecular; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism
D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496350:Fgfr1 protein, rat; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma