0955-2235:9? $15.00
,i:, 1993Pergamon PressLtd
Pro,sye.\s in Growth Factor Rrsearch.
Vol. 4. pp. 107-120, 1992
Printed in Great Britain. All rights reserved.
INTERACTIONS
OF FGFs WITH
CELLS
Dominique Ledoux, Leila Gannoun-Zaki
TARGET
and Denis Barritault*
Laboratoire de Recherche sur la Croissance Cellulaire, La Reparation et la Regeneration
Tissulaires, Jeune Formation INSERM n 9014
Universite Paris XII-Val de Marne
Avenue du General de Gaulle, 94010 Creteil Cedex, France
Growth factors play a key role in cellular communication. a necessary step for the
development ofpluricellular
organisms. Thejbroblast
growth factors (FGF) are among
these polypeptides andhave seven known members: FGF I to FGF 7 which are also known
as acidic FGF, basic FGF, translation products of oncogenes hst, int 2, FGFS, FGF6 and
FGF 7 or keratinoc.vte growth factor (KGF) respectivelyfl].?
The best known and the
most abundant in normal adult tissues are acidic and basic FGFs, or FGF I and 2
respectively, which have been subjected to extensive studies both in vitro and in vivo.
These two factors have almost ubiquitous distribution and a wide spectrum of biological
activity including action on cellular proltferation
and differentiation.
as well as
neurotrophic and angiogenic properties[l].
These different activities are induced by
triggering spec$c receptors present at the surface of the target cell. Following this
interaction, the FGF-receptor
complexes are internalized and activate intracellular
pathways. An important effort of investigations has been produced to characterize these
receptors and intracellular pathways. It is the purpose of this review to present this work
which willfocus on FGFs I and 2. The existence of two classes of interactions has been
reported as early as 1987 (52,53.54] suggesting the presence of high and low r@init~~
receptors for FGFs.
Keywords:FGF, receptor, heparan sulfate, internalization.
HIGH AFFINITY
Biochemical
RECEPTORS TO FGFs 1 AND 2
Characterization
and Cellular
Distribution
The presence of high affinity receptors for FGFs 1 and 2 has been reported for many
cell types as shown in Table 1 in agreement with previous observations describing a
biological activity of FGF 1 on these cells [I]. These receptors are characterized
*To whom correspondence should be addressed.
tThe accepted nomenclature after the New York Academy of Sciences Meeting in La Jolla, CA. January
1618, 1991.
107
108
D. Ledoux et al.
TABLE 1. Identification of cellular receptor to FGFs 1 and 2.
References
Endothelial cells
Hepatoma cells
Myoblasts
Vascular smooth muscle
Fibroblasts (3T3)
Fibroblasts (BHK)
Fibroblasts (CCL39)
Chondrocytes
Lens epithelial cells
Fetal neurons
External segment from retina
Adrenocortical
Bladder tumor
Neuroblastoma
MCF7 breast cell
Pheochromocytome (PC12)
FGFI,FGF:!
FGF 1
FGF I
FGF 1
FGF I
FGF I
FGF 1
FGF 2
FGF l,FGF2
FGF 2
FGF 2
FGF 2
FGF 2
FGF l,FGF2
FGF 2
FGF I
FGF 2
FGF 2
FGF l,FGF2
24
108
IO,38
109
10.38
9,38,52
3.9.52.53
52
51
15
2
55
82
11
57
56
I IO
by apparent dissociation constants ranging from 10 PM to 600 PM for both forms of
FGFs. The number of sites per cell varies from 2000 to over 100 000 according to the
cell type studied. Cross-linking
experiments followed by polyacrylamide
gel
electrophoresis of the complexes formed between labelled FGF and the putative
receptors allow the identification
of several molecular entities which can bind
specifically to FGFs 1 and 2.
According to the cell types, the apparent molecular weight of these entities range
from 105 to 165 kDa. The absence of modification of the electrophoretic migration
patterns after treatment with reducing agents suggests that these high affinity binding
sites have monomeric structures [2,3].
Further studies indicate that FGF 2 receptors on BHK cells are glycosylated on
asparagine residues [4] and that the glycosylated moities (25-30 kDa) are important for
proper FGF-receptor recognition. Different degrees of glycosylations are believed to
explain some of the variations observed in the molecular weights of these receptors as
mentioned above [5]. Despite this heterogeneity, the great majority of cellular receptors
for FGF is common to FGF 1 and FGF 2 [&lo]. Only very few cases have been
reported where a specific biological property was induced by receptors which were not
recognized by both FGFs. As an example, we can mention a cell line derived from
bladder carcinoma epithelium where FGF 1 was able to induce cellular changes in
morphology and in cellular motility by interacting with high affinity receptors which
could not be detected with FGF 2 [l 11.
A particular high affinity receptor to FGF 1 has been identified on parathyroid cells
[12]. This receptor contains several heparan sulfate chains which represent 10-l 5% of
the molecular mass and are needed for the recognition and the proper binding of FGF
1.
The variation in the number of FGF receptors appears as being an important event
Interactions
of FGFs
with Target Cells
IO9
in some biological processes such as cellular differentiation or embryonic induction. In
the course of myogenic differentiation,
receptors to FGFs are expressed during
myoblast proliferation and gradually disappear when cells stop proliferating, align and
fuse [13,14]. Terminal differentiation
of chondrocytes is also associated with a
reduction in the detectable receptors to FGF 2 [15]. In the developing Xenopus embryo,
maximal expression of FGF 2 receptors occurs at stage 8 in association with
mesodermal induction [16]. In the chicken, the number of receptors remains constant
until day 7, then drastically drops [ 171.
112vitro studies indicate that the number of FGF receptors could be regulated by
cellular density [3,18,19] or by other molecules such as phorbol esters [20]. A
diminution
in the number of receptors is also observed after FGF binding to its
receptor and subsequent internalization [3,21,22]. FGF affinity for their receptors can
also be modulated positively or negatively by a whole range of molecules. Heparin
increases FGF I affinity to its receptors [23-251 while protamine, suramin and several
basic proteins inhibit FGF 2 receptor binding [26-281.
Purification and Primary Structure
Like other membrane proteins, cell surface receptors are difficult to purify in a
biological active form, i.e. to bind to FGF. Several forms of FGF receptors have been
partially or totally purified from various sources: human hepatoma cells [29], epithelial
lens cells [30], adult rat brain [31], bovine brain [32], 6 and 7 day old chick embryos
[33,34].
All purification procedures include affinity chromatographies
on WGA and on
immobilized FGF. Purified receptors were obtained with molecular weights between
100 and 160 kDa.
However, only protein sequence information was obtained from a purified form of
the FGF receptor from more than 20,000 7 day old chick embryos [34]. This sequence
information was identical to parts of primary sequences of the product of theflg gene
(@s-like gene) [35]. A portion of this gene was previously isolated from a cDNA bank
gene from human endothelial cells and it presented homology with the proto-oncogene
~fins.
Based on this homology, a clone with the whole cDNA was isolated and the entire
sequence of FGF 2 chicken receptor was deduced. Analysis of this primary sequence
indicated that this trans-membrane protein possessed a tyrosine kinase domain and an
organization analogous to other tyrosine kinase receptors [36].
Up to now. several other groups have identified multiple forms of FGF receptors
presenting sequence homology withJEg. Four distinct families of receptors have been
described, namely: FGFRl (f7g), FGFR2 (bek), FGFR3 and FGFR4 [37].
TISSUE DISTRIBUTION
OF FGF RECEPTORS AND THEIR mRNAs
Parallel studies were performed to characterize FGF receptors from cell cultures or
from membrane preparations from chick or mouse embryos [33,34,38], mouse placenta
[39], bovine brain [40] or various adult guinea pig tissues [41,42]. These receptors
possess analogous characteristics to those identified from cell cultures. Kd values are
from lo-30 pM for FGF 2 and loo-180 pM for FGF 1 as well as proteic entities with
110
D. Ledmu et ul.
molecular weights ranging from 125 to 200 kDa. Messenger RNA transcripts coding
for FGFRI, FGFR2 and FGFR3 are found in most adult tissues of adult guinea pig,
rat and mice [42-451. FGFR4 mRNA presents a more restricted distribution and is
mainly found in the lung [46,47]. However, in adult tissues, the proteins corresponding
to these mRNA transcripts are difficult to detect. Indeed, it was not possible to combine
cross-linking or immunoblots to detect high affinity receptors for FGFs in membranes
of liver, kidney, stomach, lung, intestine or spleen although the mRNA was detected
[41,42,48,49]. In contrast, high affinity receptors could be easily detected in adult brain
membranes [4042].
In order to compare possible homologies between these high affinity brain derived
FGF receptors and the other families of FGFR, covalent complexes between FGF and
these membrane receptors were immuno-precipitated
with anti-FGFRl
and antiFGFR2 antibodies. The results obtained indicated that brain derived high affinity
receptors are immunologically
distinct from FGFRl and FGFR2 although these two
forms of receptors are functional in the brain but present in minor quantities [48].
Measurement of the content of mRNA transcripts for FGFRl, FGFR2 and FGFR3
also indicates that these transcripts are no more abundant in adult brain than in other
tissues [42,43,45]. Altogether, these results suggest the existence of another form of
high affinity FGF receptor in adult brain different from those already known. These
receptors could be similar to those lacking tyrosine kinase activity [33,50]. The presence
of large amounts of high affinity receptors for FGFs only in adult brain compared to
other adult organs suggests that these factors may not only play a role in homeostasis
or tissue repair but may also fulfil other task functions in the nervous system e.g. a
neurotrophic function, which could be mediated through specific neuronal receptors.
LOW AFFINITY
BINDING
SITES TO FGFs 1 AND 2
A second family of interaction sites for FGF 1 and 2 has been described as low affinity
binding sites on a large number of cell types including fibroblasts [51-531, endothelial
cells [52,54], epithelial cells [52], neurons [55], tumoral cells such as bladder carcinoma
cells [I 11, breast cancer cell line [56] and neuroblastoma
cells [57]. Basement
membranes were also shown to contain low affinity binding sites which were detected in
membranes from embryonic [58], adult [59] or tumoral tissues [60]. These binding sites
are characterized by an apparent Kd of between 2-20 nM and a number per cell ranging
from 0.5 x 10h to several million. Incubation of the cells with pg/ml quantities of
heparin or heparan sulfate inhibits the interaction of basic FGF with these low affinity
sites while other glycosaminoglycans (GAG) such as dermatan, keratan or chondroitin
sulfate have no effect [53]. Furthermore, interaction of FGF 2 with these low affinity
binding sites is strongly reduced when the cells are pre-treated with heparinase [5153,588601. These results suggest that low affinity binding sites are related to
proteoheparan sulfates. Proteoheparan sulfates are essentially localized in cellular
membranes and in extracellular matrices and represent nearly as much as 70% of
matritial glycosaminoglycans [61]. Proteoheparan sulfates bind specifically FGF 1 and
FGF 2. They have been identified from murine sarcoma [60], endothelial cells and their
conditioned medium [62,63] or their extracellular matrix [64]. Two major entities have
been characterized: a proteoglycan of 250 kDa which appears to be a plasmic
membrane component and an 800 kDa which belongs to the extracellular matrix.
Interactions
?f‘FGFs with Target Cells
111
Recently, a 200 kDa proteoheparan sulfate which can specifically bind FGF 2 hasbeen
described associatedto bone marrow cell membranesvia a phosphatidyl-inosito1[65].
Another step in the understanding of the structures of low affinity FGF binding sites
was reached with the cloning of the proteic core of a membrane proteoheparan sulfate
(FGF-HSPG) [66]. FGF-HSPG was isolated from a cDNA bank of hamster
fibroblasts on the basisof the ability of its glycosaminoglycan (GAG) chains to bind
FGF 2. The 33 kDa core protein has an extracellular domain containing 6 potential
sites for GAG chains, a unique trans-membrane domain and a short cytoplasmic
domain (34 residues) with no particular specific sequencesuch as a tyrosine kinase
domain.
The primary sequence of hamster FGF-HSPG presents 85% analogy with the
sequenceof a previously cloned mouse membrane proteoglycan named Syndecan [67].
Syndecan is a polymorphic molecule with heparan and chondroi’tin sulfate chains
associated to a 31 kDa trans-membrane polypeptide. This proteoglycan is mainly
found at the surface of epithelial cells from mature tissues(skin, liver and mammary
gland) and interacts with several other constituents of the matrix (fibronectin, collagen
I, 111,IV, thrombospondin) and FGF 2 [68]. Expression of Syndecan during early
mouse embryonic life indicates that this proteoglycan is present at all the stagesof
development (4 cell stagesto 8.5 days of embryo life) and has different localization at
different stages[69]. Moreover, although the size of the Syndecan core protein remains
constant during the early mouse development, the size of the intact proteoglycan does
change. thus indicating developmental alterations in its glycosaminoglycan composition.
It is now clearly establishedthat both forms of FGFs I and 2 are found in significant
amounts in extracellular matrices interacting with proteoheparan sulfates [70-741
although it is not excluded that other matrix components can also take part in the
storage of these growth factors by interacting with FGF.
Matrix bound FGFs are needed for endothelial cell growth as demonstrated by
using anti-FGF 2 antibodies to block their growth [75]. Like in the FGF-heparin
complex, the FGF bound to proteoheparan sulfate is protected against proteolysis [62]
and its biological activity potentiated [64]. The major functions attributed to matrix
associatedproteoheparan sulfates are a protecting role and a site for storage of FGFs.
These ideas can be enforced by studies of tissue distribution of mRNAs coding for
FGFs. Indeed, although these factors were isolated from a wide range of different
tissuesin large amounts, their mRNAs are practically undetectable except in brain
tissues [76,77]. This suggests that under normal conditions, there is a very weak rie ww
synthesis of FGFs and that these factors bound to proteoheparan sulfates are
protected from proteolysis and can become bioavailable to act locally after being
releasedfrom their matritial storage places [78,79]. This releasecould be due to either
partial or total proteolysis of the matrix by specific proteases secreted by cells. This
hypothesis was studied with the model of the mammary tumor derived cell line MCF 7
which mainly secretedcathepsin D under estrogen stimulation. In this study, cathepsin
D could liberate FGF 2 from its matrix storage places and this factor which was still
biologically active could stimulate MCF 7 cells to proliferate [56]. Heparinase or
heparitinase can also releasematrix bound FGF and other enzymes, such asurokinase
or phospholipase C, can generate the formation of a soluble heparan sulfate-FGF 2
complex in the culture medium of endothelial cells or bone marrow cells [63,65].
More recent works have found that the role of either matrix or cellular bound
112
D. Ledoux et ul.
proteoheparan sulfate can be extended from one natural storage function to a role in
the FGF-receptor recognition. Using mutant cells which were deficient in heparan
sulfates, Yayon et al. [80] have shown that FGF 2 could not bind to its high affinity
receptor vg). Similarly, heparitinase treatment of skeletal muscle, adenocortical cells
or of brain membranes induces the loss of the ability for FGFs to bind to their high
affinity receptors, to simulate cell proliferation and to repress myoblast terminal
differentiation [48,8 1,821. Hence proteoheparan sulfates would also act as accessory
molecules which after complexing to FGFs would present the growth factor in a
biologically active form to its high affinity receptor. Interestingly, this mechanism
doesn’t seem to induce a conformation change of the protein as shown for FGF 1 by a
variety of spectroscopic techniques [83]. Furthermore, the presence of heparan sulfate
may not always be an absolute prerequisite to obtain proper binding for FGF to its
high affinity receptors [33]. Using a ligand blotting technique, these authors have shown
that a purified 150 kDa receptor containing no heparan sulfate chain could specifically
retain FGF 2.
INTERNALIZATION
OF FGFs 1 AND 2
As for many other growth factors, interaction with their cellular receptors at 37” C
yields to a rapid internalization of the receptor-factor complex and is followed by a
decrease or down-regulation in the number of receptors at the cell surface. Similar
observations were performed with FGFs added on fibroblast, astrocytes, neurons and
human, bovine or mouse endothelial cells [3,22,5 I,84871.
FATE OF FGF 1 AND FGF 2 AT 37” C
Internalization
of FGF 2 by Chinese hamster lung fibroblasts (CCL39 cells) after
binding to its cell surface receptors has been originally shown to be remarkably
resistant to degradation [52]. Indeed, after 2 h of incubation at 37” C on CCL39 cells,
two fragments of 9 and 6 kDa were formed [86]. Further studies indicate that within 30
min after internalization,
these fragments can be progressively detected and that they
stay stable in the cell for more than 13 h [86]. Similar studies were performed with FGF
2 on endothelial cells [22,84] and on neurons and astrocytes [87]. According to the cell
studied, different size of fragments were obtained. In bovine capillary endothelial cells,
a 16 kDa fragment is found [22] while others report the formation of fragments of 15,
10 and 8 kDa in human microvascular endothelial cells [84]. Three fragments of 15.5,9
and 4 kDa are also described in astrocytes and neurons [87]. Kinetic studies indicate
that the 15.5 kDa fragment is first detected after 4 h and is still present after 24 h while
the 9 and the 4 kDa fragments appear after 4 h in astrocytes and 16 h in neurons but
remain present for 24 and 48 h in astrocytes and neurons, respectively. Similar,
although less extensive, studies were performed with FGF 1. In endothelial cells, FGF
1 is cleaved in two fragments of 15 and 10 kDa after 2 h at 37” C. The fragments remain
stable in the cells after 12 h of incubation [85].
Interactions
CELLULAR
of‘FGFs
113
with Target Cells
LOCALIZATION
OF FGFs 1 AND 2 AND THEIR
FRAGMENTS
Lysosomotrophic
agents such as chloroquine inhibit FGF degradation in endothelial cells [84,85] and fibroblasts [86]. These results suggest that the FGF cleavage
takes place in lysosomal vesicles. According to the state of proliferation, exogenously
added FGF 2 was localized in the cytoplasm as well as accumulated in nuclear and
nucleolus. This nuclear uptake was correlated with overall stimulation of transcription
and more specifically with increased transcription of genes coding for ribosomal RNA
in the GO to Gl transition phase [88]. A long form of FGF 2 (18.4 kDa) is found in the
nucleolus of exponentially endothelial cells but is not detected in the nucleus of
confluent cells [89], while a 16.5 kDa form of FGF 2 is detected at all times in the
cytoplasm. Similar results were obtained with Swiss 3T3 cells where 18.4 kDa and 16.5
kDa forms were detected in both the nucleus and cytoplasm but with a higher
proportion of the 18.4 kDa in the nucleus than in the cytoplasm [90]. Stimulation of
quiescent 3T3 cells by [“51] FGF 2 resulted after 8 h in a nuclear accumulation
representing 8% of the total cellular incorporation [90]. The cellular compartmentalization of FGF 2 has also been further studied by indirect immuno-fluorescence
techniques and confirmed that a fraction of FGF 2 was concentrated in the nucleus of
growing 3T3 cells, showing bright staining of the nucleoli and diffuse staining of the
nucleoplasmic network [90]. In neurons and astrocytes, internalized FGF 2 is mostly
found associated with lysosomes and endosomes after 4 or 16 h. However, FGF 2 is
also associated with the nuclear chromatin [87].
Endogenous FGF 2 also accumulates in the nuclei of various FGF 2 producing cells
and of NIH 3T3 or BHK-21 cells transfected with cDNA expressing FGF 2 [91-961.
Recently the interacting DNA sequences for FGF 2 were isolated from FGF 2
synchronously stimulated 3T3 cells using a DNA-protein
cross-linking agent and a gel
retardation technique from restriction enzymes (Dra-Hat III) DNA fragments. With
this approach, the FGF 2 interacting nucleolus DNA sequences were shown to
correspond to (GT) 28 putative ZDNA sequences located upstream of the spacer
promoter [90].
Less is known about FGF 1. Indirect evidence of nuclear localization of FGF 1 has
been provided using deletion mutants which were deprived of their putative nuclear
translocation sequence NYKKPKL.
These FGF 1 mutants bind to their high affinity
receptors and enter the cells but fail to be mitogenic [97].
THE
INTERNALIZATION
OF FGF IS MEDIATED
AFFINITY RECEPTORS
BY HIGH
AND LOW
Evidence on the involvement of both high and low affinity receptors in the
internalization pathway of FGF 2 comes from two different sets of experiments. At
equilibrium and at concentrations close to the Kd value, FGF 2 is internalized via high
affinity receptors (4700 molecules/cell) and via low affinity receptors (10” molecules/cell)
[5 11.However, at higher concentration, internalization does not reach an equilibrium
state and no apparent saturation was observed, suggesting other internalization
pathways [51]. The second set of evidence comes from the need of long lasting
interaction of FGF 2 with endothelial cells to induce proliferation [98].
Cells shifted from 4” C to 37“ C in the presence of FGF 2 rapidly internalize FGF 2
114
D. Ledou.u et (11.
and high affinity receptors are shown to down-regulate in the first l-2 h [3,22]. However,
a parallel and continuous internalization
occurs after 68 h and addition of
neutralizing antibodies more than 2 h after the treatment with FGF 2 also abolishes the
mitogenic affect of FGF [98]. This late internalization pathway mediated by low affinity
receptors was further supported by experiments where soluble heparin inhibited the
prolonged internalization of FGF 2 and its binding to low affinity sites with the same
potency as by heparinase treatment which also inhibited the prolonged internalization
of FGF 2 [99]. The same authors also show that internalization of low affinity binding
sites resulted in a partial protection of FGF from lysosomal degradation suggesting
that bFGFcel1 surface-proteoheparan
sulfate complexes are maintained during the
internalization
process. The involvement of both high and low binding sites in
internalization
has also been studied in neurons and astrocytes in the presence of
heparin to inhibit low affinity binding and wheat germ agglutinin which inhibits
high affinity binding [87]. The three degradation fragments of FGF 2 described for
astrocytes and neurons were only obtained when cells were treated with heparin,
suggesting that internalization in these cells was only mediated via the high affinity
receptors. To visualize the intracellular complexes. photoactivatable
cross-linking
agents (HSAB) have been used [loo, 1011. FGF 2 can be covalently fixed to several sites
on fibroblasts ranging from 80 to 320 kDa. These sites differ from the FGF high affinity
receptors described in the first part of this review. The same molecular weight
complexes are also formed once the FGFs have been internalized. After pre-treatment
of the cells with heparitinase, the surface or intracellular complexes are no longer
detected, suggesting that heparan sulfate proteoglycans are involved in these
complexes.
FURTHER DIRECTIONS
Many questions concerning the FGF signal transduction pathways remain to be
answered. FGF is internalized via its high and low affinity receptors into the lyososomal
compartments
but nothing is known on the routes to the nuclei. Can both
internalization pathways also provide FGF for the nuclei? What are the mechanisms
for FGF transportation to the nuclei? An intracellular 24 kDa protein putative FGF
transporter has been recently described [ 1021. This protein binds covalently to FGF 1
after internalization
and could transport FGF 1 to the nuclei. Another possibility
where a soluble receptor could transport FGFs has also been proposed [ 1031. Why is
only part of the internalized FGF found associated to the nuclei? Is it the same
mechanism that regulates nuclear translocation of endogenously produced FGF 2, in
this case, is FGF associated with chromatin or with the whole nucleus? For some
authors, translocation towards the nucleus of higher molecular weight forms of
endogenously produced FGF 2 (22.5 kDa and 24 kDa) could be due to extension of the
NH2 terminal part of the factor [ 104,105]. This sequence has a particularly rich content
in glycine and arginine similar to the nuclear targeting sequence (NTS) [ 1061. However,
the demonstration of the presence of the three forms of endogenously produced FGF 2
in the nucleus indicates that the extended NH2 terminal sequence is not always needed
for nuclear targeting [94].
Among the DNA sequences bound to FGF 2, the (AC 28: GT 28) rDNA region with
a potential ZDNA formation is of particular interest. The location of the (GT 28) FGF
Intrructions
oj‘FGFs
with
Target
ll_S
Cells
2 binding site upstream from the spacer promoter suggests that this site might act as a
regulatory element of rDNA transcription.
Furthermore (GT) genomic repeated
sequences are widely spread and may account for the pleiotrophic effect of FGF 2 in
target cells [107]. However, other DNA binding sequences might also be involved and it
would be of interest to see if other members of the FGF families interact with the same
sequences. Other questions concern the possible different mechanisms of internalization mediated by the high and low affinity receptors, the role of the tyrosine kinase and
the function, if any, of the long lasting FGF fragments. Is there also a transportation of
the high or low affinity receptors to the nuclei? Do these receptors also interact with the
DNA? Other questions concerning the function of the matrix in the control of cell
growth and differentiation via the storage and the transportation of the FGFs to their
cellular targets must also be addressed. Most of these questions should be answered in
the coming years if one considers the effort of investigation which has been, and is still
being, given to the understanding of this family of growth factors.
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