Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells

Abstract

Stably transfected PC12 cell lines expressing similar amounts of chimeric receptors composed of the extracellular domain of the human platelet-derived growth factor (PDGF)␤ receptor and the transmembrane and intracellular domains of the fibroblast growth factor receptors (FGFRs) 1, 3, and 4 undergo ligand-induced differentiation. The FGFR1 chimera (PFR1) is the most potent of the three, and PFR4 requires more frequent (every 24 hr) addition of ligand to maintain the response. Both PFR1 and -3 also show significant ligand-independent autophosphorylation but PFR4 does not. All of the chimeras activated phospholipase C␥, Shc, FGFR substrate (FRS)2, and the mitogen-activated protein kinases, ERK1 and 2. PFR4 was moderately weaker in stimulating these effects as well; PFR1 and -3 were comparable. None of the chimeras induced Sos association or were coprecipitated with Shc. Cotransfection of a dominantnegative Shc derivative, with tyrosine at 239, 240, and 317 replaced with phenylalanine, in the PFR-expressing cells was without effect on PDGF-induced neurite outgrowth. The same derivative substantially inhibited the response of these cells to NGF. These results indicate that FGFR1, 3, and 4 (i) are capable of signaling in a similar fashion; (ii) primarily use FRS2 and, perhaps, PLC␥; and (iii) do not utilize Shc. The results also suggest that the principal difference between FGFR1, 3, and 4 is in the strength of the tyrosine kinase activity and that qualitative differences in signaling capacity are likely to be less important.

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

“…FGFR1 and FGFR3 have different signaling properties in some cell types in vitro (Wang et al 1994;Lin et al 1996;Naski et al 1996). These differences may be attributable to differences in the strength of the tyrosine kinase signal but not to the specific signaling pathway activated (Raffioni et al 1999). Consistent with this, both receptor kinase domains appear to have similar activities when expressed in proliferating chondrocytes in vivo (Wang et al 2001).…”

FGF signaling in the developing endochondral skeleton

“…Both FGFR1 and FGFR3 kinase domains appear to have similar activities when expressed in growth plate chondrocytes in vivo [115]. Therefore, observed differences between these receptors must be attributable to differences in the strength of the tyrosine kinase signal rather than the specific signaling pathway activated [116]. This property of FGF signaling in chondrocytes supports the hypothesis that the proliferating chondrocyte itself is uniquely responsive to an FGFR signal.…”

Association of the Atypical Protein Kinase C-interacting Protein p62/ZIP with Nerve Growth Factor Receptor TrkA Regulates Receptor Trafficking and Erk5 Signaling

“…With respect to TrkA, it has been shown that Shc is required for this pathway (13,34,38). The failure of Shc to compete for with p62 for binding to TrkA reveals that p62 activates the B pathway independently of this site.…”