1
Department of Vascular Biology, The Scripps Research Institute, 10550 N.
Torrey Pines Road, La Jolla, CA 92037, USA
2
Department of Pharmacology, University of Pennsylvania School of Medicine,
3620 Hamilton Walk, Philadelphia, PA 19104, USA
*
Author for correspondence (e-mail:
schwartz{at}scripps.edu
)
![]() |
SUMMARY |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Tyrosine kinase, Signal transduction, Growth control, Cell adhesion
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Integrin-dependent signaling pathways |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the context of growth regulation, it is essential to distinguish
transient effects seen in replated cells from sustained effects in stably
adherent cells. Investigators have often studied integrin signaling by plating
suspended cells on ECM proteins, which is analogous to acute stimulation of
starved cells with growth factors. This protocol initiates transient
stimulation of many pathways, including Rac, Cdc42 and their downstream
kinases; tyrosine kinases or substrates such as Src and Shc; Ras and JNK; and
phosphoinoside 3-kinase (PI3K) and its downstream pathways (for reviews see
Giancotti and Ruoslahti, 1999;
Cary et al., 1999
). These
events are likely to be important in regulation of cell migration,
cytoskeletal organization or gene expression; however, transient stimulation
of pathways in early G1 is generally not sufficient to induce
S-phase entry. For example, ERK and PI3K must be active in mid-G1
phase for cells to enter S phase, and transient PI3K activity in early
G1 phase is even dispensible for cell cycle progression (Meloche et
al., 1992
; Jones et al.,
1999
; Gille and Downward,
1999
; Jones and Kazlauskas,
2001
). Similarly, Bohmer et
al. reported that cell adhesion is required throughout most of G1
phase (Bohmer et al., 1996
).
Among the integrin-dependent signals characterized to date, stimulation of
tyrosine phosphorylation of focal adhesion kinase (FAK), p130cas
and paxillin, PIP 5-kinase activity and Na+/H+
antiporter activity are sustained as long as cells remain adherent (reviewed
by Schwartz et al., 1995
).
There are older data suggesting that Na+/H+ exchange is
important (Schwartz et al.,
1995
), but in most cases
causal relationships between these sustained integrin-dependent signals and
the cell cycle machinery have yet to be established. FAK has been the most
studied, and the results of studies linking FAK to G1 phase cell
cycle progression are outlined below.
Potentiation of growth factor receptor signaling by integrins also
contributes critically to cell cycle progression. This cooperation begins at
the level of the receptors themselves. Cell adhesion increases the number of
PDGF receptors by blocking their degradation by a ubiquitin-dependent pathway
(Baron and Schwartz, 2001).
Integrins also physically associate with growth factor receptors and enhance
receptor activation (Schneller et al.,
1997
; Jones et al.,
1997
; Moro et al.,
1998
).
Under many conditions, growth factor activation is substantial in
non-adherent cells (McNamee et al.,
1993; DeMali et al.,
1999
), in which cases
integrins enhance downstream signaling. The ERK MAP kinase cascade is
regulated by integrins at multiple points. One study showed that, although
overall PDGFR activation was unaffected by adhesion, phosphorylation at a
single site and binding of RasGAP to the PDGFR was decreased in cells plated
on FN compared to polylysine, leading to increased Ras and ERK activation on
FN (DeMali et al., 1999
). In
other studies, activation of Ras was unaffected by adhesion, but activation of
Raf and subsequently ERK was strongly adhesion-dependent (Lin et al.,
1997
; Howe and Juliano,
2000
). Additionally, others
reported that activation of MEK by Raf requires integrinmediated adhesion
(Renshaw et al., 1997
), or
that sustained activation of ERK by growth factors requires cell adhesion
(Roovers et al., 1999
). These
discrepancies suggest that the ERK cascade has multiple adhesion-dependent
steps whose importance varies between cells or experimental conditions.
Nevertheless, it is agreed that sustained ERK activation requires cooperative
signaling between RTKs and integrins.
Interestingly, FAK participates in multiple growth regulatory events.
Integrin-mediated effects on FAK control transcription of the adapter protein
IRS-1 (Lebrun et al., 2000).
This effect appears to be mediated in part by effects on JNK activity, in
general agreement with a previous study reporting that JNK mediates FAK
regulation of cell cycle progression (Oktay et al.,
1999
). Although proliferation
was not assayed, FAK also mediates integrin enhancement of signaling by growth
factors to activate MEK and ERK (Renshaw et al.,
1999
). A recent paper showed
that FAK can mediate activation of the ERK cascade in cells replated on
fibronectin (FN) via Rap1 and B-Raf rather than Ras and Raf-1 (Berberis et
al., 2000
). However, this paper
did not directly evaluate the integrin-growth-factor synergy pathway by
comparing adherent and suspended cells. Finally, inhibition of protein kinase
A delayed the decline in both FAK phosphorylation and Raf activity after cell
detachment (Howe and Juliano,
2000
). These results suggest
that FAK is a multifunctional protein that plays a critical role in the
integrin enhancement of mitogenic signaling.
A number of other RTK pathways are sensitive to cell adhesion. Growth
factor induction of the Rac pathway is integrin dependent (del Pozo et al.,
2000). In this context, RTKs
still activate Rac in suspended cells, but the activated Rac fails to target
to the plasma membrane and interact with its effectors. Activation of PI3K and
Akt in response to EGF is also attenuated in non-adherent cells (Khwaja et
al., 1997
), as is growth
factor activation of JNK (Short et al.,
1998
). Finally, PDGF
activation of protein kinase C and downstream events was decreased in
non-adherent cells, despite equivalent phosphorylation of phospholipase C
(McNamee et al., 1993
). In
this system, detachment from the ECM led to a decline in activity of PIP
5-kinase and cellular levels of phosohatidylinositol 4,5-bisphosphate
(PtdIns(4,5)P2), which is the substrate for phospholipase
C. As PtdIns(4,5)P2 is a major determinant of the actin
cytoskeleton and membrane targeting of pleckstrin homology domain proteins
(Toker, 1998
), a decrease in
its levels in suspended cells could have widespread effects on signaling
pathways. Interestingly, actin polymerization itself is a determinant of gene
expression through the serum-response element, which is found in the promoters
of many cytoskeletal and cell cycle regulatory genes (Sotiropoulos et al.,
1999
). Integrins induce
polymerization and organization of actin through both physical protein-protein
interactions that anchor actin filaments at sites of adhesion and through
signaling pathways such as PtdIns(4,5)P2 and Rho family
GTPases (reviewed by Schoenwaelder and Burridge,
1999
). Thus, actin itself
could also contribute to integrin effects on cell cycle progression. These
findings are summarized in Fig.
1.
|
Finally, we note that, although the major model for integrin signaling is
positive regulation due to ligation and crosslinking of integrins, several
labs have observed that unoccupied integrin 5ß1 in nonadherent
cells has dominant effects that inhibit growth or survival (Giancotti and
Ruoslahti, 1990
; Symington,
1992
; Varner et al.,
1995
). In an interesting
twist, the CDK inhibitor INK4a was found to sensitize cells to
detachment-induced apoptosis by increased transcription of integrin
5ß1; the unoccupied integrin then promotes cell death (Plath et
al., 2000
). Thus, an
alternative model is that unoccupied or unclustered integrins transmit signals
that are terminated by integrin occupancy or clustering. Accordingly, the
integrin ß3 cytoplasmic domain was recently shown to interact with and
activate caspase 8 to induce death of endothelial cells, and clustering
negatively regulated this interaction (Stupack and Cheresh, submitted). Thus,
although many studies show integrin stimulation of cytoplasmic pathways, these
do not in principle distinguish direct activation from reversal of an
inhibition. Both mechanisms probably contribute to cell survival and growth to
some extent.
![]() |
Regulation of cyclins and CDKs |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The induction of cyclin D1 mRNA has most frequently been attributed to the
activation of ERKs (reviewed by Roovers and Assoian,
2000). In most cases,
activation of the Ras-Raf-MEK-ERK cascade induces cyclin D1 gene expression.
Conversely, inhibition of the Ras pathway inhibits cyclin D1 gene expression.
Several studies have shown that the induction of cyclin D1 requires only
moderate ERK activity, but the activity must be sustained for several hours
(Weber et al., 1997
).
Sustained ERK signaling in response to integrin and RTK synergism (Roovers and
Assoian, 2000
) may therefore
explain the joint growth factor plus ECM requirement for cyclin D1
expression.
A sustained ERK signal, although necessary, is not sufficient to induce
cyclin D1 protein. Sustained ERK signaling increases cyclin D1 expression in
adherent but not suspended CCL39 cells (Le Gall et al.,
1998). Thus, adhesion must
make other contributions to G1 progression. One such contribution
is evident from studies indicating that the transport of ERK from the
cytoplasm to the nucleus is dependent upon cell adhesion (Danilkovitch et al.,
2000
). Alternatively, PI3K is
required for the expression and stability of cyclin D1 (Gille and Downward,
1999
; Takuwa et al.,
1999
; Diehl et al.,
1998
). As discussed above,
both integrins and RTKs contribute to PI3K activity. The relative importance
of ERK signal duration, ERK nuclear translocation and PI3K activity in the
induction of cyclin D1 among different cell types remains to be
determined.
Integrin signaling also stimulates the translation of cyclin D1 mRNA, and
this effect seems to be the major mechanism by which integrins increase cyclin
D1 levels in endothelial cells (Huang et al.,
1998). Very recent studies
indicate that activation of Rac by integrins is important for the translation
of cyclin D1 in endothelial cells (F. Giancotti, personal communication),
again suggesting that regulation of cyclin D1 expression is likely to involve
more than MEK/ERK activation. Interestingly, integrins mediate the
translocation of activated Rac to the plasma membrane (see above) and the
movement of mRNA and ribosomes to focal adhesions (Chicurel et al.,
1998b
). These complementary
effects suggest that subcellular compartmentalization by the ECM might
integrate different integrin-dependent events affecting cell proliferation.
Overexpression of activated Rac also stimulates cyclin D1 gene expression, at
least in fibroblasts (Gille and Downward,
1999
; Joyce et al.,
1999
; Page et al.,
1999
). Rac may therefore have
cell-specific effects on the synthesis of cyclin D1 mRNA and protein. Rac
activity and function are regulated by integrins (see above), which again
suggests that regulation of cyclin D1 expression is likely to involve more
than MEK/ERK activation.
A few studies have assessed the upstream signaling mechanisms by which
integrins might regulate cyclin D1. Overexpression of wild-type and dominant
negative FAK cDNAs showed that integrin-dependent phosphorylation of
FAK plays an important role in the phosphorylation of ERK and induction of
cyclin D1 (Zhao et al., 1998).
The results with FAK agree well with studies implicating FAK in
integrin/RTK-dependent ERK activation (Renshaw et al,
1999
). Others have shown that
overexpression of ILK leads to the expression of cyclin D1 (Radeva et al.,
1997
). Given that ILK is
downstream of PI3K (Delcommenne et al.,
1998
), these results agree
with studies implicating PI3K signaling in control of cyclin D1
expression.
In addition to the stimulation of cyclin D1 synthesis, integrin signals are
important for the downregulation of CDK inhibitors of the p21 family.
p21cip1 is induced in early G1 phase. Its induction
requires strong ERK activity (reviewed by Roovers and Assoian,
2000), which is dependent upon
synergistic signaling by growth factor receptors and integrins (discussed
above). In mid-late G1 phase, the levels of p21cip1 and
p27kip1 are downregulated coincidently with activation of
cyclin-ECDK2. This downregulation is impaired when integrin signaling
is blocked (reviewed by Roovers and Assoian,
2000
). The mechanisms
underlying these effects are poorly understood, but ERK seems not to be not
directly involved (Bottazzi et al.,
1999
; Olson et al.,
1998
). Several studies have
implicated Rho in the downregulation of both p21cip1 and
p27kip1 (Weber et al.,
1997
; Olson et al.,
1998
; Adnane et al.,
1998
; Laufs et al.,
1999
), but there is little
evidence to support a direct link between integrin signaling and Rho
activation. Indeed, direct analysis of Rho-GTP levels shows that integrins
have complex effects on Rho activity and do not simply stimulate Rho activity
throughout G1 phase (Ren et al.,
1999
).
![]() |
Integrin- and matrix-specific effects |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Integrin v is among those
subunits that, along with
5
and
1, associate with Shc and caveolin and promote DNA synthesis (Wary
et al., 1996
; Wary et al.,
1998
). These associations
unexpectedly depend on sequences in the
subunit transmembrane and
extracellular domains. Although the transient activation of ERK that occurs
downstream of Shc appears to be too brief to account for transit through
G1 phase, the association could mediate other growth-promoting
signals. Integrin
vß3 also shows a particular ability to cooperate
with bFGF to promote long term ERK activation and angiogenesis (Elcieri et
al., 1998
), to activate the
NF-
B pathway (Scatena et al.,
1998
) and to induce calcium
entry into cells (Schwartz and Denninghoff
1994
). In several of these
studies, other integrins failed to induce similar effects despite similar
abilities to promote adhesion and cytoskeletal organization.
In addition to integrin vß3, integrin
5ß1 (the
classical fibronectin receptor), associates with caveolin and Shc (as
mentioned above) and also promotes DNA synthesis (Wary et al.,
1996
). In myoblasts, elevated
5ß1 expression promotes ERK activation and proliferation, whereas
elevated levels of integrin
6ß1 (a laminin receptor) inhibit ERK
and promote withdrawal from the cell cycle and differentiation (Sastry et al.,
1999
). In astrocytoma cells,
adhesion to vitronectin or fibronectin promotes activation of PI3K and its
association with FAK much better than does adhesion to collagen (Ling et al.,
1999
). Integrins
5ß1 and
vß3 also promote responsiveness of vascular
smooth muscle cells to insulin-like growth factor by a distinct mechanism:
secretion of IGF binding protein-5 (IGFBP-5; Zheng et al.,
1998
). Adhesion of these cells
to collagen or laminin promotes cell growth much less well but the difference
is eliminated by addition of soluble IGFBP-5
Different collagen receptors, however, have distinct growth regulatory and
signaling properties. Integrin 1ß1 in skin fibroblasts promotes
cell proliferation, apparently by the caveolin-dependent signaling pathway
discussed above (Pozzo et al.,
1998
). By contrast,
stimulation of integrin
2ß1 does not promote proliferation in
endothelial cells and fibroblasts (Wary et al.,
1996
; Pozzo et al.,
1998
; Davey et al.,
1999
). Interestingly, integrin
2ß1 activates p38 MAP kinase (Ivaska et al.,
1999
), and p38 is thought to
inhibit transcription of the cyclin D1 promoter (Lavoie et al.,
1996
). However, the inhibitory
effect of integrin
2ß1 on cell proliferation may be cell-type
specific;
2ß1 promotes mammary epithelial tube formation and
proliferation more effectively than does integrin
1ß1 (Zutter et
al., 1999
). These findings are
summarized in Fig. 2.
|
![]() |
Organization of the extracellular matrix |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A few studies have examined the role of the collagen matrix in cell
proliferation. Aortic smooth muscle cells proliferate poorly on polymerized
collagen gels (conditions in which cell spreading is minimal), which
correlated with poor downregulation of p27kip1 (Koyama et al.,
1996). Conversely, monomeric
collagen films supported efficient cell spreading, p27kip1
downregulation and G1 phase cell cycle progression. Subsequent
studies in this system revealed that FN/
5ß1 binding mediates the
proliferation of smooth muscle cells on collagen films and that the
inefficient proliferation of smooth muscle cells on collagen gels reflects
impaired formation of FN fibrils and downregulation of integrin
5ß1 (Raines et al.,
2000
; E. W. Raines et al.,
personal communication). These new results fit nicely with studies indicating
that cell spreading on collagen, in the absence of FN/
5ß1
signaling, does not support cell proliferation (Wary et al.,
1996
; Davey et al.,
1999
).
In addition to chemical signaling, integrin ligation results in the
organization of the actin cytoskeleton and generation of tensional forces
(mechanical signaling) that contribute to G1 phase progression
(reviewed by Huang and Ingber,
1999; Koyama et al.,
1996
; Raines et al.,
2000
; Chicurel et al.,
1998a
). Early studies showed
that when hepatocytes are plated on increasing amounts of fibronectin,
attachment per se is sufficient to promote progression through early
G1 phase but cell spreading is required to complete progression
into S phase (Hansen et al.,
1994
). Subsequently,
micropatterned matrices were used to demonstrate that the effect of cell
spreading is independent of the density of integrin clusters in capillary
endothelial cells (Chen et al.,
1997
). More recently, these
techniques were used to show that cell spreading is required for the
translation of cyclin D1 and downregulation of p27kip1 in
endothelial cells (Huang et al.,
1998
). These results support
the premise that the proliferative effect of cell spreading reflects the
development of mechanical tension within the cell that is specifically
dependent on the ligation of integrins (Huang et al.,
1998
; Chicurel et al.,
1998).
The Grinnell laboratory has studied effects of mechanical tension in
fibroblasts within collagen gels. When cells are embedded within gels that
resist tensional forces, ERK is phosphorylated, cyclin D1 is expressed, p27 is
downregulated and the cells cycle when stimulated with growth factors.
Disruption of mechanical tension leads to the loss of actin stress fibers, the
inactivation of ERKs, the loss of cyclin D1 and the upregulation of
p27kip1 (Rosenfeldt and Grinnell,
2000; H. Rosenfeldt and F.
Grinnell, personal communication). Several laboratories have used cytochalasin
D to disrupt the actin cytoskeleton and cell spreading, and these experiments
typically result in an inhibition of integrin signaling and integrin-dependent
cell cycle progression. However, when fibroblasts are cultured in collagen
gels, cell spreading can persist even when stress fibers have been
disassembled. Using this approach, the Grinnell lab showed that cell spreading
in the absence of actin stress fibers is not sufficient to support ERK
activation, cyclin D1 expression, p27kip1 downregulation or cell
proliferation. Others studies discussed above also indicate that cell
spreading itself is not sufficient to support proliferation (Wary et al.,
1996
; Davey et al.,
1999
). Together, the results
to date support the idea that both chemical and mechanical signals play roles
in stimulating progression through G1 phase._
Mechanical and chemical signaling appear to be linked. Cells respond to
mechanical forces by activating a substantial range of signaling pathways,
including the ERK and JNK pathways (reviewed by Shyy and Chien,
1997). Among these effects,
increasing mechanical tension stimulates FAK phosphorylation (Yano et al.,
1996
; Tang et al.,
1999
). Cell-generated tension
might therefore feed back on focal adhesions to influence the activity of FAK,
which could promote cell proliferation through the pathways discussed above.
Effects of tension on ERK, PI3K and Rho family GTPases could also contribute.
These results may be relevant to the wide range of systems in which malleable
matrices inhibit cell proliferation but promote differentiation (reviewed by
Adams and Watt, 1993
).
![]() |
Conclusions and summary |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Many questions remain about the full range and mechanisms of these effects; however, two areas of greatest ignorance stand out. First, despite extensive data on pathways controlled by integrins, the proximal mechanisms by which integrins signal remain poorly defined. Second, the contribution of mechanical effects to proliferation and the mechanisms of mechanotransduction are very poorly understood. We anticipate rapid progress in these areas and eagerly await the answers.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Adams, J. C. and Watt, F. M. (1993). Regulation
of development and differentiation by the extracellular matrix.
Development 117,1183
-1198.
Adnane, J., Bizouarn, F. A., Qian, Y., Hamilton, A. D. and
Sebti, S. M. (1998). p21(WAF1/CIP1) is upregulated by the
geranylgeranyltransferase I inhibitor GGTI-298 through a transforming growth
factor beta- and Sp1-responsive element: involvement of the small GTPase rhoA.
Mol. Cell. Biol. 18,6962
-6970.
Baron, V. and Schwartz, M. (2001). Cell adhesion regulates ubiquitin-mediated degradation of the platelet derived growth factor ß. J. Biol. Chem. (in press).
Berberis, L., Wary, K. K., Fiucci, G., Liu, F., Hirsch, E., Brancaccio, M., ALtruda, F., Tarone, G. and Giancotti, F. G. (2000). Distinct roles for the adapter protein Shc and focal adhesion kinase in integrin signaling to Erk. J. Biol. Chem. (in press).
Bohmer, R. M., Scharf, E. and Assoian, R. K. (1996). Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1. Mol. Biol. Cell 7, 101-111.[Abstract]
Borges, E., Jan, Y. and Ruoslahti, E. (2000).
Platelet derived growth factor receptor ß and vascular endothelial growth
factor receptor 2 bind to the ß3 integrin through its extracellular
domain. J. Biol. Chem.
275,39867
-39873.
Bottazzi, M. E., Zhu, X., Bohmer, R. M. and Assoian, R. K.
(1999). Regulation of p21(cip1) expression by growth factors and
the extracellular matrix reveals a role for transient ERK activity in
G1 phase. J. Cell Biol.
146,1255
-1264.
Bourdoulous, S., Orend, G., MacKenna, D. A., Pasqualini, R. and
Ruoslahti, E. (1998). Fibronectin matrix regulates activation
of RHO and CDC42 GTPases and cell cycle progression. J. Cell
Biol. 143,267
-276.
Cary, L. A., Han, D. C. and Guan, J. L. (1999). Integrin-mediated signal transduction pathways. Histol. Histopathol. 14,1001 -1009.[Medline]
Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. M. and
Ingber, D. E. (1997). Geometric control of cell life and
death. Science 276,1425
-1428.
Chicurel, M. E., Chen, C. S. and Ingber, D. E. (1998a). Cellular control lies in the balance of forces. Curr. Opin. Cell Biol. 10,232 -239.[Medline]
Chicurel, M. E., Singer, R. H., Meyer, C. J. and Ingber, D. E. (1998b). Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature 392,730 -733.[Medline]
Danilkovitch, A., Donley, S., Skeel, A. and Leonard, E. J.
(2000). Two independent signaling pathways mediate the
antiapoptotic action of macrophage-stimulating protein on epithelial cells.
Mol. Cell. Biol. 20,2218
-2227.
Davey, G., Buzzai, M. and Assoian, R. K.
(1999). Reduced expression of (alpha)5(beta)1 integrin prevents
spreading-dependent cell proliferation. J. Cell Sci.
112,4663
-4672.
Delcommenne, M., Tan, A., Gray, V., Rue, L., Woodgett, J. and Dedhar, S. (1998). Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin linked kinase. Proc. Natl. Acad. Sci. USA (in press).
Del Pozo, M. A., Price, L. S., Alderson, N., Ren, X. D. and
Schwartz, M. A. (2000). Adhesion to the extracellular matrix
regulates the coupling of the small GTPase Rac to its effector Pak.
EMBO J. 19,2008
-2014.
DeMali, K. A., Balciunaite, E. and Kazlauskas, A.
(1999). Integrins enhance platelet-derived growth factor (PDGF)
dependent responses by altering the signal relay enzymes that are recruited to
the PDGF ß receptor. J. Biol. Chem.
274,19551
-19558.
Diehl, J. A., Cheng, M., Roussel, M. F. and Sherr, C. J.
(1998). Glycogen synthase kinase-3beta regulates cyclin D1
proteolysis and subcellular localization. Genes Dev.
12,3499
-3511.
Elicieri, B. P., Klemke, R., Stromblad, S. and Cheresh, D.
A. (1998). Integrin vß3 requirement for sustained
mitogen-activated protein kinase activity during angiogenesis. J.
Cell Biol. 140,1255
-1263.
Giancotti, F. G. and Ruoslahti, E. (1990).
Elevated levels of the 5ß1 fibronectin receptor suppress the
transformed phenotype of CHO cells. Cell
60,849
-859.[Medline]
Giancotti, F. G. and Ruoslahti, E. (1999).
Integrin signaling. Science
285,1028
-1032.
Gille, H. and Downward, J. (1999). Multiple ras
effector pathways contribute to G(1) cell cycle progression. J.
Biol. Chem. 274,22033
-22040.
Hansen, L. K., Mooney, D. J., Vacanti, J. P. and Ingber, D. E. (1994). Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth. Mol. Biol. Cell 5, 967-975.[Abstract]
Honda, H., Oda, H., Nakamoto, T., Honda, Z. I., Sakai, R., Suzuki, T., Saito, T., Nakamura, K., Nakao, K., Ishiwara, T. et al. (1998). Cardiovascular anomaly, impaired actin bundling and resistance to src-induced transformation in mice lacking p130cas. Nat. Genet. 19,361 -365.[Medline]
Howe, A. K. and Juliano, R. L. (2000). Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activated kinase. Nat. Cell Biol. 2, 593-600.[Medline]
Huang, S. and Ingber, D. E. (1999). The structural and mechanical complexity of cell-growth control. Nat. Cell Biol. 1,E131 -E138.[Medline]
Huang, S., Chen, C. S. and Ingber, D. E.
(1998). Control of cyclin D1, p27(Kip1), and cell cycle
progression in human capillary endothelial cells by cell shape and
cytoskeletal tension. Mol. Biol. Cell
9,3179
-3193.
Ilic, D., Furuta, Y., Kanazawa, S., Takeda, N., Sobue, K., Nakatsuji, N., Nomura, S., Fujimoto, J., Okada, M., Yamamoto, T. et al. (1995). Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377,539 -544.[Medline]
Ivaska, J., Reunanen, H., Westermarck, J., Koivisto, L., Kahari,
V. M. and Heino, J. (1999). Integrin 2ß1 mediates
isoform-specific activation of p38 and upregulation of collagen gene
transcription by a mechanism involving the
2 cytoplasmic tail.
J. Cell Biol. 147,401
-415.
Jones, P. L., Crack, J. and Rabinovitch, M.
(1997). Regulation of tenascin C, a vascular smooth muscle cell
survival factor that interacts with the vß3 integrin to promote
epidermal growth factor receptor phosphorylation and growth. J.
Cell Biol. 139,279
-293.
Jones, S. M. and Kazlauskas, A. (2001). Growth-factor-dependent mitogenesis requires two distinct phases of signalling. Nat. Cell Biol. 3, 165-172.[Medline]
Jones, S. M., Klinghoffer, R., Prestwich, G. D., Toker, A. and Kazlauskas, A. (1999). PDGF induces an early and a late wave of PI3-kinase activity, and only the late wave is required for progression through G1. Curr. Biol. 9, 512-521.[Medline]
Joyce, D., Bouzahzah, B., Fu, M., Albanese, C., D'Amico, M.,
Steer, J., Klein, J. U., Lee, R. J., Segall, J. E., Westwick, J. K. et al.
(1999). Integration of Rac-dependent regulation of cyclin D1
transcription through a nuclear factor-kappaB-dependent pathway. J.
Biol. Chem. 274,25245
-25249.
Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H.
and Downward, J. (1997). Matrix adhesion and Ras
transformation both activate a phosphoinositide 3-OH kinase and protein kinase
B/Akt cellular survival pathway. EMBO J.
16,2783
-2793.
Kornberg, L. J., Earp, H. S., Turner, C. E., Prockop, C. and Juliano, R. L. (1991). Signal transduction by integrins: increased protein tyrosine phosphorylation caused by integrin clustering. Proc. Natl. Acad. Sci. USA 88,8392 -8396.[Abstract]
Koyama, H., Raines, E. W., Bornfeldt, K. E., Roberts, J. M. and Ross, R. (1996). Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell 87,1069 -1078.[Medline]
Laufs, U., Marra, D., Node, K. and Liao, J. K.
(1999). 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors
attenuate vascular smooth muscle proliferation by preventing rho
GTPase-induced down-regulation of p27(Kip1). J. Biol.
Chem. 274,21926
-21931.
Lavoie, J. N., L'Allemain, G., Brunet, A., Muller, R. and
Pouyssegur, J. (1996). Cyclin D1 expression is regulated
positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.
J. Biol. Chem. 271,20608
-20616.
Le Gall, M., Grall, D., Chambard, J. C., Pouyssegur, J. and Van Obberghen-Schilling, E. (1998). An anchorage-dependent signal distinct from p42/44 MAP kinase activation is required for cell cycle progression. Oncogene 17,1271 -1277.[Medline]
Lebrun, P., Baron, V., Hauck, C. R., Schlaepfer, D. D. and
Obberghen, E. V. (2000). Cell adhesion and focal adhesion
kinase regulate insulin receptor substrate-1 expression. J. Biol.
Chem. 275,38371
-38377.
Lin, T. H., Chen, Q., Howe, A. and Juliano, R. L.
(1997). Cell anchorage permits efficient signal transduction
between ras and its downstream kinases. J. Biol. Chem.
272,8849
-8852.
Ling, J., Liu, Z., Wang, D. and Gladson, C. L. (1999). Malignant astrocytoma cell attachment and migration to various matrix proteins is differentially sensitive to phosphoinositide inhibitors. J. Cell. Biochem. 73,533 -544.[Medline]
Manabe, R., Oh-e, N. and Sekiguchi, K. (1999).
Alternatively spliced EDA segment regulates fibronectin-dependent cell cycle
progression and mitogenic signal transduction. J. Biol.
Chem. 274,5919
-5924.
McNamee, H. M., Ingber, D. E. and Schwartz, M. A. (1993). Adhesion to fibronectin stimulates inositol lipid synthesis and enhances PDGF-induced inositol lipid breakdown. J. Cell Biol. 121,673 -678.[Abstract]
Meloche, S., Seuwen, K., Pages, G. and Pouyssegur, J. (1992). Biphasic and synergistic activation of p44mapk (ERK1) by growth factors: correlation between late phase activation and mitogenicity. Mol. Endocrinol. 6,845 -854.[Abstract]
Miyamoto, S., Akiyama, S. K. and Yamada, K. M. (1995). Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science 267,883 -885.[Medline]
Moro, L., Venturino, M., Bozzo, C., Silengo, L., Altruda, F.,
Beguinot, L. and Tarone, G. (1998). Integrins induce
activation of the EGF receptor: role in MAP kinase induction and
adhesion-dependent cell survival. EMBO J.
17,6622
-6632.
Oktay, M., Wary, K. K., Dans, M., Bilge, R. B. and Giancotti, F.
G. (1999). Integrin-mediated activation of focal adhesion
kinase is required for signaling to Jun NH2-terminal kinase and
progression through the G1 phase of the cell cycle. J.
Cell Biol. 145,1461
-1469.
Olson, M. F., Paterson, H. F. and Marshall, C. J. (1998). Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature 394,295 -299.[Medline]
Page, K., Li, J., Hodge, J. A., Liu, P. T., Vanden Hoek, T. L.,
Becker, L. B., Pestell, R. G., Rosner, M. R. and Hershenson, M. B.
(1999). Characterization of a Rac1 signaling pathway to cyclin
D(1) expression in airway smooth muscle cells. J. Biol.
Chem. 274,22065
-22071.
Plath, T., Detjen, K., Welzel, M., von Marsha, Z., Murphy, D.,
Schirner, M., Weidenmann, B. and Rosewicz, S. (2000). A novel
function for the tumor suppressor p16INK4a: induction of anoikis
via upregulation of the 5ß1 fibronectin receptor. J.
Cell Biol. 150,1467
-1477.
Pozzo, A., Wary, K. K., Giancotti, F. G. and Gardner, H. A.
(1998). Integrin 1ß1 mediates a unique
collagen-dependent proliferation pathway in vivo. J. Cell
Biol. 142,587
-594.
Radeva, G., Petrocelli, T., Behrend, E., Leung-Hagesteijn, C.,
Filmus, J., Slingerland, J. and Dedhar, S. (1997).
Overexpression of the integrin-linked kinase promotes anchorage-independent
cell cycle progression. J. Biol. Chem.
272,13937
-13944.
Raines, E. W., Koyama, H. and Carragher, N. O.
(2000). The extracellular matrix dynamically regulates smooth
muscle cell responsiveness to PDGF. Ann. New York Acad.
Sci. 902,39
-51.
Ren, X. D., Kiosses, W. B. and Schwartz, M. A.
(1999). Regulation of the small GTP-binding protein Rho by cell
adhesion and the cytoskeleton. EMBO J.
18,578
-585.
Renshaw, M. W., Ren, X. D. and Schwartz, M. A.
(1997). Activation of the MAP kinase pathway by growth factors
requires integrin-mediated cell adhesion. EMBO J.
16,5592
-5599.
Renshaw, M. W., Price, L. S. and Schwartz, M. A.
(1999). Focal adhesion kinase mediates the integrin signaling
requirement for growth factor activation of MAP kinase. J. Cell
Biol. 147,611
-618.
Roovers, K. and Assoian, R. K. (2000). Integrating the MAP kinase signal into the G1 phase cell cycle machinery. BioEssays 22,818 -826.[Medline]
Roovers, K., Davey, G., Zhu, X., Bottazzi, M. E. and Assoian, R.
K. (1999). 5ß1 integrin controls cyclin D1
expression by sustaining mitogen activated protein kinase activity in growth
factor treated cells. Mol. Biol. Cell
10,3197
-3204.
Rosenfeldt, H. and Grinnell, F. (2000).
Fibroblast quiescence and the disruption of ERK signaling in mechanically
unloaded collagen matrices. J. Biol. Chem.
275,3088
-3092.
Ruoslahti, E. (1988). Fibronectin and its receptors. Annu. Rev. Biochem. 57,375 -413.[Medline]
Sastry, S. K., Lakonishok, M., Wu, S., Truong, T. Q.,
Huttenlocher, A., Turner, C. E. and Horwitz, A. F. (1999).
Quantitative changes in integrin and focal adhesion signaling regulate
myoblast cell cycle withdrawal. J. Cell Biol.
144,1295
-1309.
Scatena, M., Almeida, M., Chaisson, M. L., Fausto, N., Nicosia,
R. F. and Giachelli, C. M. (1998). NF-B mediates
vß3 integrin-induced cell survival. J. Cell
Biol. 141,1083
-1093.
Schneller, M., Vuori, K. and Ruoslahti, E.
(1997). vß3 integrin associates with activated
insulin and PDGFß receptors and potentiates the biological activity of
PDGF. EMBO J. 16,5600
-5607.
Schoenwaelder, S. M. and Burridge, K. (1999). Bidirectional signaling between the cytoskeleton and integrins. Curr. Opin. Cell Biol. 11,274 -286.[Medline]
Schwartz, M. A. (1997). Integrins, oncogenes
and anchorage independence. J. Cell Biol.
139,575
-578.
Schwartz, M. A. and Denninghoff, K. (1994).
v integrins mediate the rise in intracellular calcium in endothelial
cells on fibronectin even though they play a minor role in adhesion.
J. Biol. Chem. 269,11133
-11137.
Schwartz, M. A., Lechene, C. and Ingber, D. E.
(1991). Insoluble fibronectin activates the Na/H antiporter by
clustering and immobilizing integrin 5ß1, independent of cell
shape. Proc. Natl. Acad. Sci. USA
88,7849
-7853.[Abstract]
Schwartz, M. A., Schaller, M. D. and Ginsberg, M. H. (1995). Integrins: emerging paradigms of signal transduction. Annu. Rev. Cell Biol. 11,549 -599.[Medline]
Sechler, J. L. and Schwarzbauer, J. E. (1998).
Control of cell cycle progression by fibronectin matrix architecture.
J. Biol. Chem. 273,25533
-25536.
Shankar, S., Davison, I., Mason, W. T. and Horton, M. A.
(1993). Integrin receptor mediated mobilization of intranuclear
calcium in rat osteoclasts. J. Cell Sci.
105, 61-68.
Sherr, C. J. and Roberts, J. M. (1999). CDK
inhibitors: positive and negative regulators of G1 phase
progression. Genes Dev.
13,1501
-1512.
Short, S. M., Talbott, G. A. and Juliano, R. L.
(1998). Integrin-mediated signaling events in human endothelial
cells. Mol. Biol. Cell
9,1969
-1980.
Shyy, J. Y. and Chien, S. (1997). Role of integrins in cellular responses to mechanical stress and adhesion. Curr. Opin. Cell Biol. 9, 707-713.[Medline]
Soldi, R., Mitola, S., Strasly, M., Defilippi, P., Tarone, G.
and Bussolino, F. (1999). Role of alphavbeta3 integrin in the
activation of vascular endothelial growth factor receptor-2. EMBO
J. 18,882
-892.
Sotiropoulos, A., Gineitis, D., Copeland, J. and Treisman, R. (1999). Signal regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98,159 -169.[Medline]
Stoker, M., O'Neill, C., Berryman, S. and Waxman, V. (1968). Anchorage and growth regulation in normal and virus-transformed cells. Int. J. Cancer 3, 683-693.[Medline]
Symington, B. E. (1992). Fibronectin receptor
modulates cyclin-dependent kinase activity. J. Biol.
Chem. 267,25744
-25747.
Takuwa, N., Fukui, Y. and Takuwa, Y. (1999).
Cyclin D1 expression mediated by phosphatidylinositol 3-kinase through
mTOR-p70(S6K)-independent signaling in growth factor-stimulated NIH 3T3
fibroblasts. Mol. Cell. Biol.
19,1346
-1358.
Tang, D., Mehta, D. and Gunst, S. J. (1999).
Mechanosensitive tyrosine phosphorylation of paxillin and focal adhesion
kinase in tracheal smooth muscle. Am. J. Physiol.
276,C250
-C258.
Toker, A. (1998). The synthesis and cellular roles of phosphatidylinositol 4,5-bisphosphate. Curr. Opin. Cell Biol. 10,254 -261.[Medline]
Varner, J. A. and Cheresh, D. A. (1996). Integrins and cancer. Curr. Opin. Cell Biol. 8, 724-730.[Medline]
Varner, J. A., Emerson, D. A. and Juliano, R. L. (1995). Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin. Mol. Biol. Cell 6,725 -740.[Abstract]
Vuori, K. and Ruoslahti, E. (1994). Association of insulin receptor substrate-1 with integrins. Science 266,1576 -1578.[Medline]
Wary, K. K., Maneiro, F., Isakoff, S. J., Marcantonio, E. E. and Giancotti, F. G. (1996). The adapter protein Shc couples a class of integrins to the control of cell cycle progression. Cell 87,733 -743.[Medline]
Wary, K. K., Mariotti, A., Zurzolo, C. and Giancotti, F. G. (1998). A requirement for caveolin-1 and associated kinase fyn in integrin-dependent signaling and anchorage-dependent cell growth. Cell 94,625 -634.[Medline]
Weber, J. D., Hu, W., Jefcoat, S. C., Jr, Raben, D. M. and
Baldassare, J. J. (1997). Ras-stimulated extracellular
signal-related kinase 1 and RhoA activities coordinate platelet-derived growth
factor-induced G1 progression through the independent regulation of
cyclin D1 and p27. J. Biol. Chem.
272,32966
-32971.
Weinberg, R. A. (1995). The retinoblastoma protein and cell cycle control. Cell 81,323 -330.[Medline]
Yano, Y., Geibel, J. and Sumpio, B. E. (1996).
Tyrosine phosphorylation of pp125FAK and paxillin in aortic endothelial cells
induced by mechanical strain. Am. J. Physiol.
271,C635
-C649.
Zhao, J. H., Reiske, H. and Guan, J. L. (1998).
Regulation of the cell cycle by focal adhesion kinase. J. Cell
Biol. 143,1997
-2008.
Zheng, B., Duan, C. and Clemmons, D. R. (1998).
The effect of extracellular matrix proteins on porcine smooth muscle cell
insulin like growth factor (IGF) binding protein-5 synthesis and
responsiveness to IGF-I. J. Biol. Chem.
273,8994
-9000.
Zutter, M. M., Santoro, S. A., Wu, J. E., Wakatsuki, T.,
Dickeson, S. K. and Elson, E. L. (1999). Collagen receptor
control of epithelial morphogenesis and cell cycle progression. Am.
J. Pathol. 155,927
-940.