* Department of Biochemistry, Albert Szent-Györgyi Medical University, Szeged, Hungary; and Department of Molecular Cell
Biology, University of Utrecht, Utrecht, The Netherlands
POLYPEPTIDE growth factors (GFs)1 play a fundamental role during embryogenesis and regeneration
(e.g., wound healing) by stimulating proliferation
and differentiation of certain cell populations. Some GFs
can be responsible also for malignant transformation and
tumor growth (e.g., FGF-4: hst1 oncogene). GF receptors
(GFRs) are generally known as plasma membrane proteins which "send" signals to the nucleus principally via
the MAPK and the JAK-STAT pathways (Karin and
Hunter, 1995 Mitogenic Effect and Developmental Appearance of
Nucleus-associated GFs
Similar to steroid and thyroid hormones, vitamin D3, and
retinoic acid, it appears that GFs may be present and function in cell nuclei. In different target cells, nuclear association was shown for FGF, EGF, NGF, PDGF, insulin, etc.
(for reviews see Burwen and Jones, 1987 The presence of radiolabeled, externally added aFGF in
the nuclear fraction appeared to correlate with stimulation
of DNA synthesis in a concentration-dependent manner in
NIH 3T3 cells (with a submaximal [3H]thymidine incorporation value at 10 ng/ml FGF-1). Correlation between nuclear association of aFGF and DNA synthesis was demonstrated also in diphtheria toxin-resistant U2 Os Dr1 cells.
Although these cells lack aFGF receptors, they were able
to internalize aFGF via their cell surface toxin receptors, if
the GF was fused to the diphtheria toxin fragments. After
extracellular administration, the aFGF-toxin label was detected in the nuclear fraction. At the same time, DNA synthesis was found to rise about fourfold (at a fairly low, 5 ng/ml aFGF-toxin). However, no significant increase in
the number of cells was observed. Therefore, it appears that although nuclear action of aFGF seems to be sufficient for triggering DNA synthesis, FGFR is indispensable
for other processes of cell proliferation (Wiedlocha et al.,
1994 However, one has to keep in mind that cell lines, transfected cells, and tumor cells most probably do not behave
and cannot be considered as normal cells. Nonetheless,
cell proliferation rate and nuclear association of bFGF was
reported to change in parallel not only in glioma cells for
example, which express transfection-derived endogenous
FGF-2, but also in primary cultures of human astrocytes stimulated with extracellular bFGF (concentration range:
0.09-2.5 nM) (Joy et al., 1997 Uptake of extracellular bFGF to the nucleus and to the
nucleolus was found to occur only in late G1 phase of the
cell cycle in growing aortic endothelial (ABAE) cells, both
by immunocytochemistry and by analysis of radioiodinated cell fractions (Baldin et al., 1990 It is important to note that autocrine and intracrine FGF
types can have different effects, which are related to their
partially different sequence and to their characteristic site
of action. From the four different forms of human FGF-2,
the low molecular mass form (with 18 kD) is an autocrine/
paracrine one. The three high molecular mass forms (with
21-22, 22.5, and 24 kD, respectively) are the intracrine
ones generated by alternative translation initiation at
CUG codon, through an internal ribosome entry process
regulated by a cis-acting mechanism (Vagner et al., 1996 Developmental studies indicated that FGF-2, known as
a maternal signal involved in mesoderm induction in amphibians, brings about mesoderm induction via Src-kinase
Laloo (Weinstein et al., 1998 Nuclear Targeting of GFs and GFRs
Recently, several data have accumulated which support
the idea of GF receptor translocation to the nucleus. For
example, three FGFR-1 variants (with 145, 118, and 103 kD,
respectively) were detected in the nucleoplasmic and in
the nuclear matrix fractions of human astrocytes and bovine adrenal medullary cells. In the majority of cells, the
immunofluorescence signals of FGF-2 and FGFR-1 appeared to colocalize in the nuclei (Stachowiak et al., 1996a According to the emerging view, NLS-bearing GFs like
FGFs presumably facilitate the nuclear import of their receptors. Theoretically, GFs do not need NLS to enter the
nucleus, since the molecular "sieves" of nuclear pores demand it only from compounds >40-45 kD. Possession of
NLSs by low molecular mass GFs implies that this may be
necessary for the nuclear import of their receptors which
can be transported "piggyback" to the nucleus in association with NLS-bearing ligands (Jans, 1994 Considering the role of high-affinity GF receptors in nuclear targeting, they are probably prerequisite for the intracellular transport of GFs to the perinuclear region during receptor-mediated endocytosis. According to the
studies of Prudovsky et al. (1996) Regarding FGFs, possible involvement of low-affinity
saccharide receptors in nuclear translocation cannot be
ruled out. Heparan sulfate proteoglycans (HSPGs) with
highly O-sulfated oligosaccharide chains are well known
to play a crucial role in the formation and in the maintenance of the active FGFR-a/bFGF complexes at the
plasma membrane (Luo et al., 1996 In NIH 3T3 cells, the constitutively activated FGFR-3
mutant kinase domains in linkage with the plasma membrane appeared to be sufficient to trigger cell proliferation
and transformation, in contrast to wild-type kinase domains, or to activated kinase domains targeted to the nucleus or to the cytoplasm (Webster and Donoghue, 1997 How could GFs and GFRs act in the nucleus? Nuclear
FGFR kinase activity is thought to have no significant role
in the induction of cell proliferation (Webster and Donoghue, 1997 Normal Cells: Anchorage-dependent GF Transport to
the Nucleus?
According to the classic view, extracellular GFs stimulate
their receptor-mediated endocytosis, which leads to degradation (or to recycling) of GF receptors. However, it is
plausible to suppose that a portion of GFs and GFRs can
escape from the endosomes or lysosomes and may reach
the nucleus. Growth hormone was demonstrated to undergo a receptor-dependent nuclear translocation via the endosomes in rat hepatocytes (Lobie et al., 1994 It is intriguing to hypothesize that actin is involved not
only in endocytosis and in the transport of endosomes to
the perinuclear area (Durrbach et al., 1996 It should be noted in this context that extracellular
matrix-dependent cytoskeletal organization supervises
GF action on proliferation of normal cells, reflected in
the well-known phenomenon of anchorage-dependent growth. Cell division is generally preceded by extensive
cell spreading (Alberts et al., 1994 All in all, it seems that a portion of internalized exogenous FGFs plus their receptors may escape degradation
and could be transported to the cell nucleus. Nuclear GF-
GFR complexes appear to stimulate cell proliferation in
certain conditions in several cell types; in addition, activation of cell line-specific genes may occur in some differentiating cells. Continuous proliferation of transformed cells
could be partially due to the continuous nuclear presence
of GFs and GFRs. Obviously, much work has to be done
to elucidate details of the nuclear targeting of GF-GFR complexes and to be able to understand their nuclear action fully.
ARTICLE
Top
Article
References
). However, in the past few years data were
accumulating to suggest that, surprisingly, nuclear targeting and action of GFs and GF receptors could occur as
well. This alternative or complementary signaling pathway
appears to be involved in the induction of cell proliferation. In addition, nuclear GF-GFR complexes may participate in the activation of cell line-specific genes as well.
Since by far the largest body of data has been published in
relation to FGF-1 and -2 (aFGF and bFGF), we have focused here on the nuclear role of these GFs.
; Jans, 1994
; Prochiantz and Theodore, 1995
; Jans and Hassan, 1998
; on
FGFs: Mason, 1994
; M.K. Stachowiak et al., 1997
). Although the idea of nuclear GFs is more or less accepted, the functional significance is generally debated based on
some reports. For example, activation of the Raf-MAPK
pathway was shown to be sufficient and necessary for
transduction of the aFGF mitogenic signal in BaF3 hematopoietic cells (Huang et al., 1995
). Still, several data indicate that nuclear localization of FGFs may be required
for the mitogenic effect in certain conditions in different cell types.
). Consistent with this idea, DNA synthesis was accompanied by cell proliferation only in cells which possess
aFGF receptors or if the toxin-resistant cells were transfected with a FGFR (Wiedlocha et al., 1996
).
). These observations support
the idea that nuclear translocation of GFs could be related
to mitogenesis in normal, nontransformed cells as well.
). Nuclear association of FGF-2 was also observed in mid-late G1 phase in
proliferating epiphyseal plate chondrocytes (Kilkenny and
Hill, 1996
), suggesting a controlled nuclear entry of GFs around the restriction point of the cell cycle.
).
These intracrine forms, which have a longer, arginine-rich
NH2-terminal with at least two possible short nuclear localization sequences (NLSs) (Gly-Arg-Gly-Arg-Gly-Arg),
are preferentially targeted to the nucleus (Quarto et al.,
1991
). In contrast, the 18-kD form has only a weak or
cryptic short NLS, and is found predominantly in the cytoplasm (Quarto et al., 1991
; Davis et al., 1997
). Only the
short bFGF form can be released from the cell, and can,
therefore, interact with the plasma membrane FGFR. Surprisingly, when intracrine bFGF types were expressed in
NIH 3T3 cells, high proliferation rates and growth in soft
agar were observed, even in the presence of mutant cell
surface bFGF receptors lacking the Tyr kinase domain (Bikfalvi et al., 1995
). This reflects a plasma membrane receptor-independent pathway, presumably via formation
of complexes between intracrine GFs and intracellular receptors (see below). In vascular smooth muscle cell lines
expressing different human bFGFs, the intracrine bFGF
forms appeared to be significantly more effective in augmenting the rate of DNA synthesis than the autocrine one
(Davis et al., 1997
). Moreover, the continuous proliferation of two glioma cell lines is suggested to be related to
the constitutive presence of endogenous FGF-2 in nuclei;
these cells were nonresponsive to extracellular GFs (Joy
et al., 1997
). Synthesis of CUG-initiated forms could be induced also in primary human skin fibroblasts, producing
normally the short bFGF form almost exclusively, by heat
shock (45°C, 15-60 min) and by oxidative stress, which is probably due to translational activation (Vagner et al.,
1996
).
) and MAP kinase (Umbhauer et al., 1995
). However, nuclear bFGF may be involved in other specific developmental phenomena, since
nuclear association of bFGF becomes restricted to some
cell populations during embryogenesis. In the mid-blastula
stage, FGF-2 was demonstrated clearly in the nuclei of the
animal hemisphere of Xenopus; in the prelarval embryo,
nuclear bFGF was shown in most head regions (including
the brain) and particularly in some muscle cells of the
trunk region (immunocytochemical study by Song and
Slack, 1994
). This is consistent with the well-known stimulatory effects of bFGF on myoblast proliferation (Burgess and Maciag, 1989
) and on proliferation plus differentiation
of neuroblasts and glial precursor cells (M.K. Stachowiak
et al., 1997
). In early chicken embryos, nuclear FGF-2 isoforms were observed in most cells of the prestreak blastodiscs during hypoblast formation and mesoderm induction. Only the hypoblasts and the blastocoelic cells seemed
to maintain their nuclear immunostaining during primitive streak formation and with the onset of gastrulation (Riese
et al., 1995
). In later phases, only a small proportion of
limb bud cells, most likely migrating myoblasts, and differentiating kidney podocytes were shown to have considerable nuclear FGF-2 (immunohistochemical study by Dono
and Zeller, 1994
).
,b). So, how could the GFR gain access into the nucleus?
; Jans and Hassan, 1998
). The concept that plasma membrane GFRs
could enter the nucleus upon extracellular GF stimulation
is supported by the accurate study of Maher (1996)
, who
demonstrated a dose- and time-dependent increase of nucleus-associated FGFR-1 immunoreactivity in Swiss 3T3
fibroblasts (onset: within 10 min, max: 1 h; concentration: 5-15-50 ng/ml). Moreover, the FGFR-1 in the nuclear
fraction was shown to bear the impermeable biotin label
of the cell surface proteins and was proven to be of full
length, verifying its plasma membrane origin. Even intracrine FGFs may enter the nucleus in complex with intracellular receptors. Consistent with this idea, several truncated forms of FGFR-1 and FGFR-2 have been described, which are devoid of the transmembrane region (Givol and
Yayon, 1992
). Furthermore, a truncated FGFR3 variant
missing the transmembrane part and half of the final Ig-like domain was shown to be characteristically associated
with cell nuclei in breast epithelial cell lines by immunocytochemistry (Johnston et al., 1995
).
on transfected L6 myoblasts, the first Ig-like loop in type 1 FGFRs may facilitate
the transport of exogenous FGF-1 to the perinuclear area,
as mostly the
, 3-loop receptor isoforms possessing this domain (and not the
isoforms lacking it) were demonstrated in the nuclear/perinuclear fraction. N-glycosylation
seems to be also important, as tunicamycin treatment significantly reduced the presence of the
receptor forms in
the nuclear/perinuclear fraction. This can be interpreted
on the basis of NLS-independent, but sugar-dependent nuclear import mechanism described by Duverger et al.
(1995)
, as GFRs are glycoproteins (M.K. Stachowiak et al., 1997
).
). Perlecan, a basal
lamina proteoglycan (Aviezer et al., 1994
), syndicans, and
glypican (Steinfeld et al., 1996
) proved to be effective in
stimulating FGF-FGFR interaction. It is thought that
HSPG and extracellular bFGF bound to FGFR might be
cotranslocated to the nucleus; HSPG could stabilize the
complex and protect it from degradation in the endocytotic vesicles and in the lysosomes (Reiland and Rapraeger, 1993
). Since glypican was observed in association with
cell nuclei (in rat neurons and in glioma cells) and, moreover, it was shown to have functional NLS (Liang et al.,
1997
), this gives further credence to the mentioned idea.
).
However, in astrocyte and glioma cultures, cell proliferation appeared to correlate with the nuclear presence of
FGFR-1. Continuously proliferating glioma cells, unresponsive to external FGF, displayed constitutive nuclear
association of FGFR-1. In contrast, astrocytes had decreasing nuclear appearance of FGFR-1 in parallel to increasing cell density in cultures approaching confluency.
Furthermore, enhanced cell proliferation rate could be
achieved in glioma cells lacking FGFR-1 by transfecting
them with the full-length receptor cDNA; thereafter, immunoreactivity of FGFR-1 was seen predominantly in association with the nucleus (E.K. Stachowiak et al., 1997
).
Both in astrocytes and in bovine adrenal medullary cells,
the nuclear FGFR was shown to retain kinase activity.
With this observation, we arrived at a basic, but currently
unresolved question.
). However, bFGF may be involved in induction
of ribosomal gene transcription via stimulation of casein
kinase-2, which is known to regulate nucleolin, a major
component of the nucleolus implicated in ribosome biogenesis. Using nuclear extracts of FM3A cells and purified
proteins, FGF-2 was shown to bind CK-2 and stimulate
its activity, resulting in an increased phosphorylation of
nucleolin (Bonnet et al., 1996
). (Enhancement of CK-2
activity reached its maximum at 10-7 M FGF-2 concentration, which was calculated to be a possible bFGF concentration in the nucleus.) Supporting these observations, rRNA was found to increase severalfold upon addition of
bFGF (0.1-1 nM) to isolated nuclei from quiescent ABAE
cells (Bouche et al., 1987
). Furthermore, GF-GFR complexes may cotransport intranuclearly acting molecules to
the nucleus, via binding to the receptor, as was suggested
for IFN-
-IFN receptor complex and STAT by Johnson et al. (1998)
.
; electron
microscopic autoradiography); its nuclear uptake could be
significantly increased upon the addition of some lysosome inhibitors, indicating an escape route from the lysosomes. It is noteworthy that FGFR-1 could be detected
only in few regions at the nuclear envelope and displayed a patchy distribution within the nucleus of bovine adrenal
medullary cells; this may reflect nuclear entry at determined membrane pores and controlled transport to special
nuclear sites (immunoelectron microscopy by Stachowiak
et al., 1996b
).
), but also in the
precise nuclear targeting of GF-GFR complexes from the
perinuclear cytoplasm, since actin is known to be present
in abundance in cell nuclei, both in the chromatin and in
the nuclear matrix fraction (Capco et al., 1982
). Furthermore, there is evidence that a GF receptor, the EGFR, is a
(direct) actin-binding protein (den Hartigh et al., 1992);
other GFRs may be linked to actin indirectly, via actin-binding proteins, during their nuclear translocation.
). Spreading is probably
necessary for nuclear translocation of GF-GFR complex
in normal cells, since only astrocytes in subconfluent cultures (and not the ones in confluent cultures in short of extracellular surface) were observed to have nuclear-associated bFGF and FGFR-1. On the contrary, in continuously
growing glioma cells, nuclear appearance of FGF-2 and
FGFR-1 was constitutive and was largely independent of
cell density (Joy et al., 1997
; E.K. Stachowiak et al., 1997
).
Finally, bFGF gene is continuously activated in glioma
cells irrespective of cell density, whereas in astrocytes
bFGF transcription is induced by subconfluency (Moffett
et al., 1996
).
![]() |
Footnotes |
---|
Address correspondence to Margit Keresztes, Department of Biochemistry, Albert Szent-Györgyi Medical University, 6701 Szeged, POB 415, Hungary. Tel.: 36-62-455-096. Fax: 36-62-455-097. E-mail: margo{at}biochem.szote.u-szeged.hu
Received for publication 3 February 1998 and in revised form 3 March 1999.
![]() |
Abbreviations used in this paper |
---|
GF, growth factor; HSPG, heparan sulfate proteoglycan; NLS, nuclear localization sequence; R, receptor.
![]() |
References |
---|
![]() ![]() ![]() |
---|
1. | Alberts, B., B. Dennis, J. Lewis, M. Raff, K. Roberts, and J.D. Watson. 1994. Normal animal cells in culture need anchorage in order to pass start. In Molecular Biology of the Cell. Garland Publishing, London and New York. 898-900. |
2. | Aviezer, D., D. Hecht, M. Safran, M. Elsinger, G. David, and A. Yayon. 1994. Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis. Cell. 79: 1005-1013 |
3. | Baldin, V., A.-M. Roman, I. Bosc-Bierne, F. Amalric, and G. Bouche. 1990. Translocation of bFGF to the nucleus is G1 phase cell cycle specific in bovine aortic endothelial cells. EMBO (Eur. Mol. Biol. Organ.) J. 9: 1511-1517 [Abstract]. |
4. | Bikfalvi, A., S. Klein, G. Pintucci, N. Quarto, P. Mignatti, and D.B. Rifkin. 1995. Differential modulation of cell phenotype by different molecular weight forms of basic fibroblast growth factor: possible intracellular signaling by the high molecular weight forms. J. Cell Biol. 129: 233-243 [Abstract]. |
5. |
Bonnet, H.,
O. Filhol,
I. Truchet,
P. Brethenou,
C. Cochet,
F. Amalric, and
G. Bouche.
1996.
Fibroblast growth factor-2 binds to the regulatory ![]() |
6. | Bouche, G., N. Gas, H. Prats, V. Baldin, J.-P. Tauber, J. Teissie, and F. Amalric. 1987. Basic fibroblast growth factor enters the nucleolus and stimulates the transcription of ribosomal genes in ABAE cells undergoing Go-G1 transition. Proc. Natl. Acad. Sci. USA. 84: 6770-6774 [Abstract]. |
7. | Burgess, W., and T. Maciag. 1989. The heparin-binding (fibroblast) growth factor family of proteins. Annu. Rev. Biochem. 58: 575-606 |
8. | Burwen, S.J., and A.L. Jones. 1987. The association of polypeptide hormones and growth factors with the nuclei of target cells. Trends Biochem. Sci. 12: 159-162 . |
9. | Capco, D.G., K.M. Wan, and S. Penman. 1982. The nuclear matrix: three-dimensional architecture and protein composition. Cell. 29: 847-858 |
10. | Davis, M.G., M. Zhou, S. Ali, D. Coffin, T. Doetschman, and G.W. Dorn II.. 1997. Intracrine and autocrine effects of basic fibroblast growth factor in vascular smooth muscle cells. J. Mol. Cardiol. 29: 1061-1072 . |
11. | Dono, R., and R. Zeller. 1994. Cell-type-specific nuclear translocation of fibroblast growth factor-2 isoforms during chicken kidney and limb morphogenesis. Dev. Biol. 163: 316-330 |
12. |
Durrbach, A.,
D. Louvard, and
E. Coudrier.
1996.
Actin filaments facilitate two
steps of endocytosis.
J. Cell Sci.
109:
457-465
|
13. |
Duverger, E.,
C. Pellerin-Mendes,
R. Mayer,
A.-C. Roche, and
M. Monsigny.
1995.
Nuclear import of glycoconjugates is distinct from the classical NLS
pathway.
J. Cell Sci.
108:
1325-1332
|
14. |
Givol, D., and
A. Yayon.
1992.
Complexity of FGF receptors: genetic basis for
structural diversity and functional specificity.
FASEB (Fed. Am. Soc. Exp.
Biol.) J.
6:
3362-3369
|
15. | den Hartigh, J.C., P.M.P. van Bergen, and en Henegouwen, A.J. Verkleij, and J. Boonstra. 1992. The EGF receptor is an actin-binding protein. J. Cell Biol. 119: 349-355 [Abstract]. |
16. |
Huang, J.,
M. Mohammadi,
G.A. Rodrigues, and
J. Schlessinger.
1995.
Reduced activation of RAF-1 and MAP kinase by a fibroblast growth factor receptor mutant deficient in stimulation of phosphatidylinositol hydrolysis.
J.
Biol. Chem.
270:
5065-5072
|
17. |
Jans, D.A..
1994.
Nuclear signaling pathways for polypeptide ligands and their
membrane receptors?
FASEB (Fed. Am. Soc. Exp. Biol.) J.
8:
841-847
|
18. | Jans, D.A., and G. Hassan. 1998. Nuclear targeting by growth factors, cytokines, and their receptors: a role in signaling? BioEssays. 20: 400-411 |
19. | Johnson, H.M., B.A. Torres, M.M. Green, B.E. Szente, K.I. Siler, J. Larkin III, and P.S. Subramaniam. 1998. Cytokine-receptor complexes as chaperones for nuclear translocation of signal transducers. Biochem. Biophys. Res. Commun. 244: 607-614 |
20. |
Johnston, C.L.,
H.C. Cox,
J.J. Gomm, and
R.C. Coombes.
1995.
Fibroblast
growth factor receptors (FGFRs) localize in different cellular compartments: a splice variant of FGFR-3 localizes to the nucleus.
J. Biol. Chem.
270:
30643-30650
|
21. | Joy, A., J. Moffett, K. Neary, E. Mordechai, E.K. Stachowiak, S. Coons, J. Rankin-Shapiro, R.Z. Florkiewicz, and M.K. Stachowiak. 1997. Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells. Oncogene. 14: 171-183 |
22. | Karin, M., and T. Hunter. 1995. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr. Biol. 5: 747-757 |
23. | Kilkenny, D., and D.J. Hill. 1996. Perinuclear localization of an intracellular binding protein related to the fibroblast growth factor (FGF) receptor 1 is temporally associated with the nuclear trafficking of FGF-2 in proliferating epiphyseal growth plate chondrocytes. Endocrinology. 137: 5078-5089 [Abstract]. |
24. |
Liang, Y.,
M. Haring,
P.J. Roughley,
R.K. Margolis, and
R.U. Margolis.
1997.
Glypican and biglycan in the nuclei of neurons and glioma cells: presence of
functional nuclear localization signals and dynamic changes in glypican during the cell cycle.
J. Cell Biol.
139:
851-864
|
25. |
Lobie, P.E.,
H. Mertani,
G. Morel,
O. Morales-Bustos,
G. Norstedt, and
M.J. Waters.
1994.
Receptor-mediated nuclear translocation of growth hormone.
J. Biol. Chem.
269:
21330-21339
|
26. |
Luo, Y.,
J.L. Gabriel,
F. Wang,
X. Zhan,
T. Maciag,
M. Kan, and
W.L. McKeehan.
1996.
Molecular modeling and deletion mutagenesis implicate the nuclear translocation sequence in structural integrity of fibroblast growth factor-1.
J. Biol. Chem.
271:
26876-26883
|
27. | Maher, P.A.. 1996. Nuclear translocation of fibroblast growth factor (FGF) receptors in response to FGF-2. J. Cell Biol. 134: 529-536 [Abstract]. |
28. | Mason, I.J.. 1994. The ins and outs of fibroblast growth factors. Cell. 78: 547-552 |
29. |
Moffett, J.,
E. Kratz,
R. Florkiewicz, and
M.K. Stachowiak.
1996.
Promoter regions involved in density-dependent regulation of basic fibroblast growth
factor gene expression in human astrocytic cells.
Proc. Natl. Acad. Sci. USA.
93:
2470-2475
|
30. | Prochiantz, A., and L. Theodore. 1995. Nuclear/growth factors. BioEssays. 17: 39-44 |
31. |
Prudovsky, I.A.,
N. Savion,
T.M. La Vallee, and
T. Maciag.
1996.
The nuclear
trafficking of extracellular fibroblast growth factor (FGF)-1 correlates with
the perinuclear association of the FGF receptor-1![]() ![]() |
32. | Quarto, N., F.P. Finger, and D.B. Rifkin. 1991. The NH2-terminal extension of high molecular weight bFGF is a nuclear targeting signal. J. Cell. Physiol. 147: 311-318 |
33. |
Reiland, J., and
A.C. Rapraeger.
1993.
Heparan sulfate proteoglycan and FGF
receptor target basic FGF to different intracellular destinations.
J. Cell Sci.
105:
1085-1093
|
34. | Riese, J., R. Zeller, and R. Dono. 1995. Nucleo-cytoplasmic translocation and secretion of fibroblast growth factor-2 during avian gastrulation. Mech. Dev. 49: 13-22 |
35. | Song, J., and J.M.W. Slack. 1994. Spatial and temporal expression of basic fibroblast growth factor (FGF-2) mRNA and protein in early Xenopus development. Mech. Dev. 48: 141-151 |
36. | Stachowiak, E.K., P.A. Maher, J. Tucholski, E. Mordechai, A. Joy, J. Moffett, S. Coons, and M.K. Stachowiak. 1997. Nuclear accumulation of fibroblast growth factor receptors in human glial cells: association with cell proliferation. Oncogene. 14: 2201-2211 |
37. | Stachowiak, M.K., P.A. Maher, A. Joy, E. Mordechai, and E.K. Stachowiak. 1996a. Nuclear localization of functional FGF receptor 1 in human astrocytes suggests a novel mechanism for growth factor action. Mol. Brain Res. 38: 161-165 |
38. | Stachowiak, M.K., P.A. Maher, A. Joy, E. Mordechai, and E.K. Stachowiak. 1996b. Nuclear accumulation of fibroblast growth factor receptors is regulated by multiple signals in adrenal medullary cells. Mol. Biol. Cell. 7: 1299-1317 [Abstract]. |
39. | Stachowiak, M.K., J. Moffett, P. Maher, J. Tucholski, and E.K. Stachowiak. 1997. Growth factor regulation of cell growth and proliferation in the nervous system. A new intracrine nuclear mechanism. Mol. Neurobiol. 15: 257-283 |
40. | Steinfeld, R., H. Van Den Berghe, and G. David. 1996. Stimulation of fibroblast growth factor receptor-1 occupancy and signaling by cell surface-associated syndecans and glypican. J. Cell Biol. 133: 405-416 [Abstract]. |
41. | Umbhauer, M., C.J. Marshall, C.S. Mason, R.W. Old, and J.C. Smith. 1995. Mesoderm induction in Xenopus caused by activation of MAP kinase. Nature. 376: 58-62 |
42. | Vagner, S., C. Touriol, B. Galy, S. Audigier, M.-C. Gensac, F. Amalric, F. Bayard, H. Prats, and A.-C. Prats. 1996. Translation of CUG- but not AUG-initiated forms of human fibroblast growth factor 2 is activated in transformed and stressed cells. J. Cell Biol. 135: 1391-1402 [Abstract]. |
43. | Webster, M.K., and D.J. Donoghue. 1997. Enhanced signaling and morphological transformation by a membrane-localized derivative of the fibroblast growth factor receptor 3 kinase domain. Mol. Cell. Biol. 17: 5739-5747 [Abstract]. |
44. | Weinstein, D.C., J. Marden, F. Carnevali, and A. Hemmati-Brivanlou. 1998. FGF-mediated mesoderm induction involves the Src-family kinase Laloo. Nature. 394: 904-908 |
45. | Wiedlocha, A., P.O. Falnes, I.H. Madshus, K. Sandig, and S. Olsnes. 1994. Dual mode of signal transduction by externally added acidic fibroblast growth factor. Cell. 76: 1039-1051 |
46. | Wiedlocha, A., P.O. Falnes, A. Rapak, R. Munoz, O. Klingenberg, and S. Olsnes. 1996. Stimulation of proliferation of a human osteosarcoma cell line by exogenous acidic fibroblast growth factor requires both activation of receptor tyrosine kinase and growth factor internalization. Mol. Cell. Biol. 16: 270-280 [Abstract]. |