Different abilities of the four FGFRs to mediate FGF-1 translocation are linked to differences in the receptor C-terminal tail

Abstract

Members of the fibroblast growth factor family bind to one or more of the four closely related membrane-spanning FGF receptors. In addition to signaling through the receptors, exogenous FGF-1 and FGF-2 are endocytosed and translocated to the cytosol and nucleus where they stimulate RNA and DNA synthesis. Here we have studied the ability of the four FGF receptors to facilitate translocation of exogenous FGF-1 to the cytosol and nucleus. FGFR1 and FGFR4 were able to mediate translocation, whereas FGFR2 and FGFR3 completely lacked this ability. By analyzing mutant FGFRs we found that the tyrosine kinase domain could be deleted from FGFR1 without abolishing translocation, whereas the Cterminal tail of the FGFRs, constituted by approximately 50 amino acids downstream of the kinase domain, plays a crucial role in FGF-1 translocation. Three amino acids residues within the C-terminal tail were found to be of particular importance for translocation. For FGFR2, the two amino acid substitutions Q774M and P800H were sufficient to enable the receptor to support FGF-1 translocation. The results demonstrate a striking diversity in function of the four FGFRs determined by their Cterminal domain.

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…Recently, Sorensen et al (2006) demonstrated that a 50 amino acid sequence downstream of the tyrosine kinase domain in FGFR1 and 4 is required for the transport of fibroblast growth factor (FGF-1) from the plasma membrane to the cytosol and nucleus. Unlike FGFR1 and 4, FGFR2 lacks this sequence and consequently does not transport FGF-1 to the cytosol and nucleus (Sorensen et al 2006).…”

“…Unlike FGFR1 and 4, FGFR2 lacks this sequence and consequently does not transport FGF-1 to the cytosol and nucleus (Sorensen et al 2006). Interestingly, mutation of two amino acids within FGFR2 (Q774M, P800H) is sufficient to allow FGFR2 to similarly transport FGF-1 (Sorensen et al 2006).…”

Phosphorylation of Fibroblast Growth Factor (FGF) Receptor 1 at Ser777 by p38 Mitogen-Activated Protein Kinase Regulates Translocation of Exogenous FGF1 to the Cytosol and Nucleus

“…The translocation of exogenous FGF1 or FGF2 into the cytosol and nucleus is a highly regulated process that requires phosphatidylinositol 3-kinase (PI3K) activity (23) and active hsp90 (52) and is strictly dependent on binding of FGF to either FGFR1 or FGFR4 (47). Furthermore, translocation was found to be cell cycle dependent (3,31,63), it can be stimulated by serum deprivation of cells (1,3,18,25,31,32,55,63), and it occurs after a several-hour delay compared to the endocytic uptake of FGF (31,47).…”

“…Furthermore, translocation was found to be cell cycle dependent (3,31,63), it can be stimulated by serum deprivation of cells (1,3,18,25,31,32,55,63), and it occurs after a several-hour delay compared to the endocytic uptake of FGF (31,47). The nuclear trafficking of FGF1 is also tightly regulated by two nuclear localization sequences (19,51), a nuclear export sequence (36), and by phosphorylation of FGF1 at Ser130 by protein kinase C␦ (PKC␦) (57).…”

“…It is not known exactly how FGF crosses the vesicular membrane and to what extent this event involves accessory proteins in addition to FGFR. Previously, we identified certain amino acid residues localized in the Cterminal tail region of FGFR that are crucial for the FGF1 translocation (47).…”