Fibroblast growth factor phosphorylation and receptors in rod outer segments.

Mascarelli, Frédéric; Raulais, Daniel; Courtois, Yves

doi:10.1002/j.1460-2075.1989.tb08351.x

Cited by 69 publications

(31 citation statements)

References 43 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, proto-oncogenes have been detected in proliferative vitreoretinal diseases (Ren et al, 2000), suggesting that FGF1 is not the only mitogen implicated in proliferative vitreoretinopathy. In addition, exogenous FGF1 was also detected associated with the extracellular matrix of the retina in the absence of any RPE proliferative pathology (Mascarelli et al, 1989), showing that exogenous FGF1 is not always associated with cell proliferation. This could be due to the trapping of exogenous FGF1 by FGF-binding proteins like the soluble form of FGFR and HSPG (Guillonneau et al, 2000).…”

Section: Discussionmentioning

confidence: 95%

Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells

et al. 2000

View full text Add to dashboard Cite

Fibroblast growth factor 1 (FGF1) induces proliferation and dierentiation in a wide variety of cells of mesodermal and neuroectodermal origin. FGF1 has nò classical' signal sequence to direct its secretion, and there has been considerable debate concerning FGF1 secretion and its role in the biological activities of FGF1. We investigated the eects of FGF1 secretion and the signalling induced by signal peptide (SP)-containing FGF1 and SP-less FGF1, on the proliferation and the apoptosis in retinal pigmented epithelial (RPE) cells. Primary RPE cell cultures were transfected with FGF1 (FGF1 cells) and SP-FGF1 (SP-FGF1 cells) cDNAs. SP-FGF1 cells secreted large amount of FGF1 and actively proliferated, whereas FGF1 and control cells did not. Secreted FGF1 induced short-term activation of both FGFR1 and ERK2, which were required for cell proliferation. In contrast, SP-FGF1 cells stopped secreting FGF1 and died rapidly, if cultured in the absence of serum. Surprisingly, FGF1 cells, but not control cells, secreted FGF1 and were resistant to apoptosis induced by serum depletion. Secreted FGF1 induced long-term activation of FGFR1 and ERK2, which was necessary to induce a constant and high level of Bcl-x production, and to induce cell survival in FGF1 cells. Downregulation of ERK2 and Bcl-x increased apoptosis. Thus, the proliferation and survival activities of FGF1 depend on the secretion of FGF1 which is determined by the cell culture conditions. Cell proliferation was SP-dependent, whereas cell survival was not. The signal peptide controls the level and duration, whispering or shouting', of ERK2 activation cells which determines FGF1 biological function and may have important implications for anti-degenerative and antiproliferative treatments. Oncogene (2000) 19, 4917 ± 4929.

show abstract

Section: Discussionmentioning

confidence: 95%

Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells

et al. 2000

View full text Add to dashboard Cite

show abstract

“…In many cases a phosphorylation site close to a nuclear localization sequence regulates nucleocytoplasmic distribution (90,98,99). aFGF is phosphorylated in living cells (18,100), and both aFGF and aFGF-DT-A are phosphorylated in vitro in a cell lysate (18). However, the nucleocytoplasmic distribution of aFGF(K132E)-DT-A was apparently regulated by PI 3-kinase in the same manner as aFGF-DT-A.…”

Section: Discussionmentioning

confidence: 99%

Requirement of Phosphatidylinositol 3-Kinase Activity for Translocation of Exogenous aFGF to the Cytosol and Nucleus

Klingenberg¹,

dłocha

Citores³

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

Acidic fibroblast growth factor (aFGF) is a potent mitogen for many cells. Exogenous aFGF is able to enter the cytosol and nucleus of sensitive cells. There are indications that both activation of the receptor tyrosine kinase and translocation of aFGF to the nucleus are of importance for mitogenesis. However, the mechanism of transport of aFGF from the cell surface to the nucleus is poorly understood. In this work we demonstrate that inhibition of phosphatidylinositol (PI) 3-kinase by chemical inhibitors and by expression of a dominant negative mutant of PI 3-kinase blocks translocation of aFGF to the cytosol and nucleus. Translocation to the cytosol and nucleus was monitored by cell fractionation, by farnesylation of aFGF modified to contain a farnesylation signal, and by phosphorylation by protein kinase C of aFGF added externally to cells. If aFGF is fused to diphtheria toxin A-fragment, it can be artificially translocated from the cell surface to the cytoplasm by the diphtheria toxin pathway. Upon further incubation, the fusion protein enters the nucleus due to a nuclear localization sequence in aFGF. We demonstrate here that upon inhibition of PI 3-kinase the fusion protein remains in the cytosol. We also provide evidence that the phosphorylation status of the fusion protein does not regulate its nucleocytoplasmic distribution. Acidic fibroblast growth factor (aFGF)1 is considered to be involved in several important physiological and pathological processes, such as angiogenesis, wound healing (1), and atheromatosis (2-6). In cell cultures it can stimulate growth, cell migration, and differentiation. As the growth factor lacks a classical signal sequence, its mechanism of secretion is still unclear, but it appears to involve a pathway different from the classical secretion pathway through the endoplasmic reticulum and Golgi apparatus (7-9). At the cell surface, aFGF binds with high affinity to transmembrane FGF-receptors (FGFR) containing a cytoplasmic split tyrosine kinase domain. There are four different genes encoding FGFR (FGFR1-4) with several different splicing variants. aFGF also binds to heparan sulfate proteoglycans at the cell surface, although with lower affinity. Upon activation, the FGFR is phosphorylated on tyrosine residues, and it activates downstream effectors such as phosholipase C␥ and the mitogen-activated protein kinase pathway. There are some conflicting data as to whether phosphatidylinositol (PI) 3-kinase is also activated (10 -13). After binding to high affinity cell surface receptors, aFGF is translocated across cellular membranes and transported to the nucleus (14 -22). The mechanism of this process is not well defined. It depends on FGFR and, at least in the case of FGFR4, also on the intactness of the C terminus of its cytosolic part. 2Human PI 3-kinases phosphorylate PI in the 3Ј position of the inositol ring and can be divided into three main classes on the basis of in vitro substrate specificity (23). Class I phosphorylates PI, PI 4-phosphate and PI 4,5-diphosphate and include...

show abstract

“…It has been recognized for some time that the retina, as well as other ocular tissues and fluids, contains substantial levels of aFGF and bFGF (26)(27)(28)(29)(30)(31). aFGF immunoreactivity has been noted within the ganglion cell and inner nuclear layers ofthe retina and within the photoreceptor cell inner and outer segments (28,32).…”

mentioning

confidence: 99%

Sequestration of basic fibroblast growth factor in the primate retinal interphotoreceptor matrix.

Hageman¹,

Kirchoff-Rempe²,

Lewis³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The interphotoreceptor matrix (IPM) occupies the extracellular space between the photoreceptors of the retina and the apical surface of the retinal pigmented epithelium. A large proportion of the IPM is composed of aqueousinsoluble glycoconjugates, including chondroitin sulfatecontaining proteoglycans, the distribution of which exhibits both apical-basal and photoreceptor cell type-specific heterogeneities. The precise function of most insoluble IPM constituents is unknown, although the available evidence suggests some may contribute to retinal adhesion or photoreceptor survival. We have now identified basic fibroblast growth factor (bFGF), or an immunologically related protein from the FGF family, within the IPM. The IPM is labeled on sections of primate retinas by a battery of polyclonal antibodies (Abs) directed against various peptide sequences of bFGF and by an Ab to bovine brain bFGF. bFGF Abs also bind to purified preparations of aqueous-insoluble IPM. AU bFGF Abs utilized cross-react with equivalent low molecular mass components of 16.5-17.5 kDa on Western blots of insoluble IPM proteins, purified bFGF, and recombinant bFGF. The Abs do not bind any aqueous-soluble IPM components, suggesting that the bFGF is normally bound to an insoluble 1PM constituent(s) in situ. The fact that bFGF is sequestered in the IPM and is located in such close proximity to the photoreceptors, the retinal pigmented epithelium, and Mueller's glia raises the strong possibility that it is synthesized by and regulates the activities of one or more of these three cell types in vivo.The fibroblast growth factors (FGFs) are a family of peptides that have been isolated from a broad range of cell types. FGFs share a number of structural, biochemical, and biological properties, the most characteristic being that they bind to heparin (1-4). The FGF family consists of acidic FGF (aFGF), basic FGF (bFGF), and a number of other related molecules that exhibit significant sequence homology to these two proteins. FGFs, like some other growth factors, are regarded as multifunctional in that they have a range of effects and activities in vitro that depend upon the target cell type (5). To date, FGFs have been shown: to influence neuronal differentiation, survival, and regeneration (6-9); to act as mitogens (10-13) and as inducing factors (14-17); to modulate protein synthesis (12,18); and to induce cell motility and migration (19). Much more is known about the effects of FGFs in vitro than under in vivo conditions.Although biochemical assays have shown that FGFs are present in a wide variety of cell types and tissues (for review, see refs. 3 and 4), only a few studies have sought to determine their specific cellular and/or extracellular distributions. Antibodies (Abs) have been used to localize bFGF to the cytoplasm of rat brain neurons (20-22) and chicken striated muscle myoblasts (23) and to the extracellular matrix of mouse hind-limb muscle (24). A recent comprehensive study of bFGF distribution in the 18-day rat fetus revealed intrace...

show abstract

Fibroblast growth factor phosphorylation and receptors in rod outer segments.

Cited by 69 publications

References 43 publications

Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells

Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells

Requirement of Phosphatidylinositol 3-Kinase Activity for Translocation of Exogenous aFGF to the Cytosol and Nucleus

Sequestration of basic fibroblast growth factor in the primate retinal interphotoreceptor matrix.

Contact Info

Product

Resources

About