Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014 USA
* Author for correspondence (e-mail: jschwarzbauer{at}molbio.princeton.edu)
![]() |
Summary |
---|
Key words: Extracellular matrix, Fibronectin, Integrin, Fibril, Receptor, Intracellular signaling
![]() |
Introduction |
---|
![]() |
Major steps in the FN matrix assembly pathway |
---|
|
|
As a dimeric ligand, FN induces integrin clustering, which brings together
bound FN and increases its local concentration. The cysteines that constitute
the dimerization site at the C-terminus are, therefore, essential for
assembly, promoting receptor clustering and FNFN interactions. There
are at least four sites for FNFN binding, and these are distributed
across the length of each subunit (Fig.
1). Interestingly, many of these sites act as partners for the
site in the N-terminal assembly domain, which perhaps explains why this is the
only FN-binding site that is essential for fibril formation. Fragments
containing the assembly domain, such as the 70 kDa N-terminal fragment
(Fig. 1), can inhibit
fibrillogenesis without affecting FNintegrin interactions
(McDonald et al., 1987;
McKeown-Longo and Mosher,
1985
; Sechler and
Schwarzbauer, 1998
), and FN lacking this domain is incapable of
assembly (Schwarzbauer, 1991
;
Sottile and Mosher, 1997
;
Sottile et al., 1991
). In
addition, during the early stages of fibril formation, the 70 kDa fragment can
be used to identify sites of assembly, where it binds to FN and colocalizes
with clustered
5ß1 integrin
(Dzamba et al., 1994
;
Wierzbicka-Patynowski and Schwarzbauer,
2002
). The existence of one essential FN-binding site enhances
control of the assembly process since all interactions depend on accessibility
to this single site. The fact that there are multiple partners for this site
suggests that the alignment of FN dimers within fibrils varies depending on
which partners are available for assembly domain binding. Variable alignment
would place the other binding domains (for heparin, cells, collagen, etc.)
into different molecular contexts and close to different `near-neighbors' on
adjacent dimers. In this way, dimer alignment would have a significant impact
on fibril complexity.
In most instances, FN assembly is initiated by integrins that recognize the
RGD and synergy sequences. Surprisingly, the specific location of the
cell-binding site within FN is not critical. Placement of repeats
III9-10 more N-terminal in place of III4-5
(Fig. 1) generated a
recombinant FN that assembled normally
(Sechler et al., 2001). An
RGD-independent mechanism acts through binding of
4ß1 integrin to
the CS1 site
within the alternatively spliced V region near
the C-terminus (Sechler et al.,
2000
). Clearly, the integrin-binding site does not need to be
centrally located for initiation and propagation of FN fibril formation.
At early stages of de novo assembly, FN fibrils are short and usually
extend between adjacent cells or from the cell to nearby substrate
(Fig. 2). These fibrils are
soluble in buffers containing 2% deoxycholate detergent. As more FN
accumulates at the cell surface, fibrils are gradually converted into a
detergent-insoluble form, and a significant proportion of these exist as
high-molecular-weight multimers
(McKeown-Longo and Mosher,
1983). Insolubility and multimerization might involve
intermolecular disulfide bonding catalyzed by the intrinsic protein disulfide
isomerase activity of FN (Langenbach and
Sottile, 1999
) or might result from highly stable
proteinprotein interactions (Chen
and Mosher, 1996
). Partial unfolding of the III9 module
of FN promotes formation of amyloid-like fibrils in vitro
(Litvinovich et al., 1998
); so
perhaps a similar process of ß-strand exchange contributes to the
detergent insolubility of the FN matrix. Further investigation of this and
other potential mechanisms is needed to decipher the process by which FN
fibrils become insoluble.
![]() |
Fibronectin activation by conformational change |
---|
Many different sites can participate in FNFN interactions
(Fig. 1), and some of these may
confer the compact conformation on the soluble protein. The N-terminal
assembly domain has the most binding partners and is able to interact with
native III1-2 (Aguirre et al.,
1994), heat-denatured III1
(Hocking et al., 1994
), the
heparin-binding domain (III12-14)
(Bultmann et al., 1998
) and a
combination of III1-2 plus heat-denatured III10
(Hocking et al., 1996
).
Interactions have also been reported between native III1 and
III7 (Ingham et al.,
1997
), as well as between III12-14 and
III2-3 (Johnson et al.,
1999
). Thus, there are numerous permutations of FNFN
interactions that can occur. It remains to be determined whether certain sites
are preferentially used in soluble versus fibrillar FN.
Availability of integrin-binding sites also appears to be regulated.
Epitopes within the cell-binding domain and the V (IIICS) region are exposed
by adsorption of FN to a solid surface or by binding of heparin, treatment
with proteases or changes in salt concentration
(Ugarova et al., 1996;
Ugarova et al., 1995
).
Alternative splicing modulates cell interactions as well. For example,
increased cell spreading and migration of HT1080 cells occurs on FN containing
the EIIIA module, suggesting that inclusion of this repeat, which resides near
the RGD and synergy sequences, improves access to cell-binding sites
(Manabe et al., 1999
).
![]() |
Exposure of binding sites |
---|
Cryptic binding sites, those that are exposed by unfolding of individual
type III modules, have also been implicated in FN assembly. The most dramatic
examples of cryptic sites are those that are detected only in denatured
fragments or peptides. Incubation of soluble FN with the III-1C peptide, which
spans about two-thirds of the III1 module, induced formation of a
multimeric form of FN that could be stretched into a fibrillar-like network
(Morla et al., 1994). One
plausible mechanism of III-1C action is that it disrupts interdomain
interactions in soluble FN and thus promotes intermolecular associations in
solution. That this peptide is able to bind to many different parts of FN
(Ingham et al., 1997
)
indicates that it might expose multiple FN-binding sites. Hocking et al. have
also identified a cryptic binding site for FN and the 70 kDa fragment in
intact III1 by heat denaturation
(Hocking et al., 1994
).
Similarly, heat-denatured III10 can bind to III1
(Hocking et al., 1996
). In
both the peptide and heat-denatured modules, the ß-sandwich structure of
the type III repeat is unfolded, and hydrophobic core residues are exposed.
Possibly, exposure of hydrophobic sequences is sufficient to provide a
platform for FN binding. Or perhaps the effects are less specific, since the
III-1C peptide also induces aggregation of fibrinogen
(Yi and Ruoslahti, 2001
), and
heat-denatured III5 is as active as heat-denatured III10
in III1 binding (Hocking et
al., 1996
). Although III1 fragments have some
assembly-related activities in vitro, it is now clear that III1 is
not essential for matrix assembly, since a recombinant FN lacking this module
forms a perfectly normal matrix (Sechler
et al., 2001
). Although there remain questions about which cryptic
sites are relevant to assembly, it is clear that binding sites are sequestered
in soluble FN and must be exposed for FN to form fibrils.
![]() |
Elasticity of FN fibrils |
---|
Several mechanisms have been proposed to explain fibril elasticity
(Erickson, 1994;
Ohashi et al., 1999
).
Straightening of FN subunits provides one mode of extension. Disruption of
interdomain interactions that contribute to the compact conformation of
soluble FN would expand the protein. This may be facilitated by `hinge'
sequences within FN. In fact, sequence gazing at the repeating FN structure
shows several sites where extra residues are inserted between repeats. The
largest of these is the alternatively spliced V region (see
Fig. 1). Interestingly, this
segment is always present in tissue FN
(Schwarzbauer et al., 1985
).
Further straightening of the zigzag connections between type III modules would
provide additional extension from 160 nm to
175 nm for each dimer
(Erickson, 1994
). Another
level of unfolding could result from unraveling of individual type III
repeats, which, unlike type I and II repeats, are not stabilized by disulfide
bonds. Modeling studies have suggested that application of sufficient force
promotes gradual unfolding of individual repeats. Breakage of hydrogen bonds
between ß-strands in type III modules could lead to partial or eventually
complete unraveling (Krammer et al.,
1999
). This has important ramifications for regulation of
cellmatrix interactions because unfolding of III10 would
include concomitant flattening of the RGD loop. Experimental support for type
III module unraveling has been provided by atomic force microscopy (AFM)
analyses where individual fragments from titin, tenascin or fibronectin have
been stretched (Oberhauser et al.,
2002
; Oberhauser et al.,
1998
; Rief et al.,
1997
).
If unfolding can occur in vivo, which parts of the molecule are likely to
be affected? FN studies show variation in the stability of individual type III
repeats in that different amounts of force are needed to unfold them. AFM data
suggest that the III1-2 pair is quite stable and unlikely to unfold
in the native protein (Oberhauser et al.,
2002), raising a question about the nature of the cryptic site in
III1. Other AFM work and computer modeling, by contrast, support
III10 unfolding at relatively low force
(Craig et al., 2001
;
Krammer et al., 1999
;
Oberhauser et al., 2002
). This
may have functional significance given that heat-denatured III10
can form a ternary complex with the 70 kDa fragment and heat-denatured
III1 (Hocking et al.,
1996
). Other regions that may be prone to unravel include
III9 (Litvinovich et al.,
1998
) and III12-13
(Oberhauser et al., 2002
).
Thus, variation in type III stability may limit the unfolded regions to
specific parts of the protein, in particular the cell- and heparin-binding
domains.
Baneyx et al. have used fluorescence resonance energy transfer (FRET) to
determine the contribution of FN elasticity to formation of matrix fibrils
(Baneyx et al., 2001;
Baneyx et al., 2002
). They
attached different fluorescent tags to free sulfhydryls in repeats
III7 and III15 and to free amines randomly along the
length of FN. Variations in FRET provide convincing evidence for
conformational changes within an FN dimer as it goes from solution to
cell-associated to fibrillar. Differences along the length of fibrils
indicated that FN dimers vary in their degrees of expansion from the compact
to the extended form. The level of FRET at some locations may also suggest
module unraveling but this is open to interpretation. Erickson has recently
argued that the majority of the FRET signals in these experiments can be
attributed to expansion of the compact conformation and not to module
unraveling (Erickson, 2003
).
Thus, although there is general agreement that FN dimers are compact in
solution and expand to an extended conformation during matrix assembly, it is
still unclear whether unfolding of individual modules contributes to fibril
elasticity.
![]() |
Elasticity and cytoskeletal contractility |
---|
Control of FN matrix by contractility may have physiological ramifications
in the vasculature. Varicose human saphenous veins show reduced deposition of
FN matrix and decreased Rho kinase expression
(Cario-Toumaniantz et al.,
2002). Platelets assemble FN fibrils when stimulated by LPA or
sphingosine 1-phosphate (Olorundare et
al., 2001
). Interactions between FN and
5ß1 integrin
contribute to full activation of Rho, whereas
vß3 and other
integrins do not substantially activate Rho
(Danen et al., 2002
) and are
less able to form dense matrix (Wennerberg
et al., 1996
; Wu et al.,
1996
). In vivo, LPA stimulation might allow integrins other than
5ß1 to support matrix assembly.
How do FN, integrins and cytoskeletal components come together to promote
fibrillogenesis? Integrins affect intracellular processes through a variety of
cytoskeletal, adapter and signaling molecules, including paxillin, vinculin,
talin, focal adhesion kinase (FAK) and Src
(Miranti and Brugge, 2002;
Schwartz et al., 1995
). In
response to integrinFN interactions in culture, some of these proteins
are differentially incorporated into two distinct protein assemblies: focal
adhesions and fibrillar adhesions (Geiger
et al., 2001
; Zamir et al.,
1999
). Focal adhesions, which are paxillin- and vinculin-rich
structures, provide cells with firm substrate attachment and points of anchor
for actin stress fibers. Fibrillar adhesions, by contrast, are rich in tensin
but not paxillin or vinculin. They form by FN-dependent movement of ligated
5ß1 integrins along stress fibers towards the cell center
(Ohashi et al., 2002
;
Pankov et al., 2000
;
Zamir et al., 2000
). This
process may mediate matrix assembly by stretching FN into fibrils from the
pool of dimers that are clustered at focal adhesions. In cultured cells,
tensin appears to be an important component of this process, because
expression of a tensin fragment blocks integrin translocation and FN
fibrillogenesis (Pankov et al.,
2000
). However, although focal adhesions and fibrillar adhesions
participate in fibril formation in vitro, matrix assembly within tissues might
use yet another type of paxillin-positive matrix contact
(Cukierman et al., 2001
;
Sechler and Schwarzbauer,
1997
). Clearly, integrins are essential mediators of FN
fibrillogenesis through their connections between FN and the actin
cytoskeleton and their effects on Rho activity. However, questions remain
about the composition of functional integrin-based connections and the effects
of extracellular environment on recruitment of intracellular components.
![]() |
Integrin signaling controls assembly |
---|
Perturbation of FN assembly by changes in intracellular pathways through
activation of Src and other oncogenes makes a significant contribution to
tumor cell phenotype. For example, increased Src expression and activity are
associated with a decrease in the amount of FN matrix
(Hynes, 1990;
Olden and Yamada, 1977
) and
with changes in cellFN interactions in human colon cancer
(Jones et al., 2002
). In at
least some cells, the ERK/MAP kinase pathway mediates the inhibitory effects
of v-Src (Ladeda et al.,
2001
), thus implicating the Ras oncogene pathway in FN matrix
regulation.
Oncogenes also affect integrin function and localization, which further
exacerbates defects resulting from loss of FN. Activation of Raf-1 downstream
of H-Ras suppresses the ability of 5ß1 integrin to mediate FN
matrix assembly (Hughes et al.,
1997
). The suppression correlates with activation of ERK, which is
similar to v-src-transformed cells. HT1080 human fibrosarcoma cells,
which have one activated N-ras allele, can be stimulated to assemble
FN matrix by activation of integrins using Mn2+ or ß1
integrin-activating antibody or by inhibition of Ras signaling through ERK
(Brenner et al., 2000
). Thus,
mutations in at least two oncogenes, ras and src, have
detrimental effects on FN matrix and, in some cells, exert their effects
through a common downstream effector, ERK.
![]() |
Integrin signals do not act alone |
---|
Syndecan-4 may play a more direct role in FN fibrillogenesis. It cooperates
with integrins to regulate Rho-dependent cell adhesion, spreading and actin
organization (Saoncella et al.,
1999). Concomitant ligation of
5ß1 integrin and
syndecan-4 increases levels of active Rho and phosphorylated FAK
(Wilcox-Adelman et al., 2002
).
Conditions that stimulate both Rho and FAK have been shown to favor FN matrix
assembly (Midwood and Schwarzbauer,
2002
).
Syndecan-4 may also act on assembly through protein kinase C (PKC). The
cytoplasmic tails of clustered syndecan-4 bind to PKC
(Horowitz and Simons, 1998;
Oh et al., 1997
). This kinase
can associate with focal adhesions in fibroblasts
(Barry and Critchley, 1994
). In
addition, PKC activation improves cell spreading and FAK phosphorylation on an
FN substrate (Vuori and Ruoslahti,
1993
) and increases binding of FN to fibroblast cell surfaces
(Somers and Mosher, 1993
).
Thus, PKC localization and activation affect processes required for
cell-mediated FN matrix assembly. In addition, PKC activation has been shown
to increase FN production and fibrillogenesis in a variety of cell types,
including pulmonary fibroblasts, retinal pigment epithelial cells, vascular
smooth muscle cells, osteoblasts, hyperglycemic mesangial cells and
Xenopus cells (Kaiura et al.,
1999
; Lee et al.,
1996
; Lin et al.,
2002a
; Lin et al.,
2002b
; Osusky et al.,
1994
; Singh et al.,
2001
; Yang et al.,
2002
). Together, these findings implicate PKC signaling in
modulation of FN assembly.
![]() |
An integrated model of FN assembly |
---|
|
Co-localization of syndecan-4 in focal adhesions increases the levels of active Rho GTPase and PKC, further reinforcing focal adhesion function. Many of these signaling pathways appear to feedback on integrins, strengthening connections through recruitment of additional components and sustained activation of signals. Together the combination of cytoskeleton and signaling inside promotes propagation of FN fibrils outside.
As FN is expanded and additional dimers are incorporated into fibrils,
intracellular components are redistributed into focal adhesions and fibrillar
adhesions (Fig. 3C). In
culture, these can be distinguished by the presence of paxillin versus tensin,
respectively. Movement of 5ß1 integrin and associated proteins
along stress fibers toward the center of the cell may aid in activating FN. In
this way, intracellular complexes might contribute to the formation of a dense
fibrillar network. Matrix complexity is derived, in part, from multiple
binding partners for the FN assembly domain, which provide different dimer
alignment options and thus lead to combinatorial variation in fibril
organization.
![]() |
Perspectives |
---|
![]() |
Acknowledgments |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
Aguirre, K. M., McCormick, R. J. and Schwarzbauer, J. E.
(1994). Fibronectin self-association is mediated by complementary
sites within the amino-terminal one-third of the molecule. J. Biol.
Chem. 269,27863
-27868.
Ali, I. U. and Hynes, R. O. (1977). Effects of cytochalasin B and colchicine on attachment of a major surface protein of fibroblasts. Biochim. Biophys. Acta 471, 16-24.[Medline]
Baneyx, G., Baugh, L. and Vogel, V. (2001).
Coexisting conformations of fibronectin in cell culture imaged using
fluorescence resonance energy transfer. Proc. Natl. Acad. Sci.
USA 98,14464
-14468.
Baneyx, G., Baugh, L. and Vogel, V. (2002).
Fibronectin extension and unfolding within cell matrix fibrils controlled by
cytoskeletal tension. Proc. Natl. Acad. Sci. USA
99,5139
-5143.
Barry, S. T. and Critchley, D. R. (1994). The
RhoA-dependent assembly of focal adhesions in Swiss 3T3 cells is associated
with increased tyrosine phosphorylation and the recruitment of both pp125FAK
and protein kinase C-delta to focal adhesions. J. Cell
Sci. 107,2033
-2045.
Bowditch, R. D., Hariharan, M., Tominna, E. F., Smith, J. W.,
Yamada, K. M., Getzoff, E. D. and Ginsberg, M. H.
(1994). Identification of a novel integrin binding site in
fibronectin: differential utilization by ß3 integrins. J.
Biol. Chem. 269,10856
-10863.
Brenner, K. A., Corbett, S. A. and Schwarzbauer, J. E. (2000). Regulation of fibronectin matrix assembly by activated Ras in transformed cells. Oncogene 19,3156 -3163.[CrossRef][Medline]
Bultmann, H., Santas, A. J. and Pesciotta Peters, D. M.
(1998). Fibronectin fibrillogenesis involves the heparin II
binding domain of fibronectin. J. Biol. Chem.
273,2601
-2609.
Bushuev, V. N., Metsis, M. L., Morozkin, A. D., Ruuge, E. K., Sepetov, N. F. and Koteliansky, V. E. (1985). A comparative study of structural properties of fibronectin and its 180 kDa fragment. FEBS Lett. 189,276 -280.[CrossRef][Medline]
Cario-Toumaniantz, C., Evellin, S., Maury, S., Baron, O.,
Pacaud, P. and Loirand, G. (2002). Role of Rho kinase
signalling in healthy and varicose human saphenous veins. Br. J.
Pharmacol. 137,205
-212.
Chen, H. and Mosher, D. F. (1996). Formation of
sodium dodecyl sulfate-stable fibronectin multimers. J. Biol.
Chem. 271,9084
-9089.
Chung, C. Y. and Erickson, H. P. (1997).
Glycosaminoglycans modulate fibronectin matrix assembly and are essential for
matrix incorporation of tenascin-C. J. Cell Sci.
110,1413
-1419.
Craig, D., Krammer, A., Schulten, K. and Vogel, V.
(2001). Comparison of the early stages of forced unfolding for
fibronectin type III modules. Proc. Natl. Acad. Sci.
USA 98,5590
-5595.
Cukierman, E., Pankov, R., Stevens, D. R. and Yamada, K. M.
(2001). Taking cell-matrix adhesions to the third dimension.
Science 294,1708
-1712.
Danen, E. H., Sonneveld, P., Brakebusch, C., Fassler, R. and
Sonnenberg, A. (2002). The fibronectin-binding
integrins alpha5beta1 and alphavbeta3 differentially modulate RhoA-GTP
loading, organization of cell matrix adhesions, and fibronectin
fibrillogenesis. J. Cell Biol.
159,1071
-1086.
Dzamba, B. J., Bultmann, H., Akiyama, S. K. and Peters, D.
M. (1994). Substrate-specific binding of the amino terminus
of fibronectin to an integrin complex in focal adhesions. J. Biol.
Chem. 269,19646
-19652.
Erickson, H. P. (1994). Reversible unfolding of
fibronectin type III and immunoglobulin domains provides the structural basis
for stretch and elasticity of titin and fibronectin. Proc. Natl.
Acad. Sci. USA 91,10114
-10118.
Erickson, H. P. (2003). Stretching fibronectin. J. Musc. Res. Cell Motil. 23,575 -580.
Erickson, H. P. and Carrell, N. A. (1983).
Fibronection in extended and compact conformations. Electron microscopy and
sedimentation analysis. J. Biol. Chem.
258,14539
-14544.
Furuta, Y., Ilic, D., Kanazawa, S., Takeda, N., Yamamoto, T. and Aizawa, S. (1995). Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene 11,1989 -1995.[Medline]
Geiger, B., Bershadsky, A., Pankov, R. and Yamada, K. M. (2001). Transmembrane extracellular matrixcytoskeleton crosstalk. Nat. Rev. Mol. Cell. Biol. 2, 793-805.[CrossRef][Medline]
George, E. L., Georges-Labouesse, E. N., Patel-King, R. S.,
Rayburn, H. and Hynes, R. O. (1993). Defects in mesoderm,
neural tube and vascular development in mouse embryos lacking fibronectin.
Development 119,1079
-1091.
Hall, A. and Nobes, C. D. (2000). Rho GTPases: molecular switches that contol the organization and dynamics of the actin cytoskeleton. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 355,965 -970.[CrossRef][Medline]
Halliday, N. L. and Tomasek, J. J. (1995). Mechanical properties of the extracellular matrix influence fibronectin fibril assembly in vitro. Exp. Cell Res. 217,109 -117.[CrossRef][Medline]
Hocking, D. C., Smith, R. K. and McKeown-Longo, P. J. (1996). A novel role for the integrin-binding III-10 module in fibronectin matrix assembly. J. Cell Biol. 133,431 -444.[Abstract]
Hocking, D. C., Sottile, J. and McKeown-Longo, P. J.
(1994). Fibronectin's III-1 module contains a
conformation-dependent binding site for the amino-terminal region of
fibronectin. J. Biol. Chem.
269,19183
-19191.
Homandberg, G. A. and Erickson, J. W. (1986). Model of fibronectin tertiary structure based on studies of interactions between fragments. Biochemistry 25,6917 -6925.[Medline]
Horowitz, A. and Simons, M. (1998).
Phosphorylation of the cytoplasmic tail of syndecan-4 regulates activation of
protein kinase Calpha. J. Biol. Chem.
273,25548
-25551.
Hughes, P. E., Renshaw, M. W., Pfaff, M., Forsyth, J., Keivens, V. M., Schwartz, M. A. and Ginsberg, M. H. (1997). Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway. Cell 88,521 -530.[Medline]
Hynes, R. O. (1990). Fibronectins. New York: Springer-Verlag.
Hynes, R. O. (1992). Integrins: versatility, modulation and signaling in cell adhesion. Cell 69, 11-25.[Medline]
Hynes, R. O. (1999). The dynamic dialogue
between cells and matrices: implications of fibronectin's elasticity.
Proc. Natl. Acad. Sci. USA
96,2588
-2590.
Ingham, K. C., Brew, S. A., Huff, S. and Litvinovich, S. V.
(1997). Cryptic self-association sites in type III modules of
fibronectin. J. Biol. Chem.
272,1718
-1724.
Ingham, K. C., Brew, S. A. and Isaacs, B. S.
(1988). Interaction of fibronectin and its gelatin-binding
domains with fluorescent-labeled chains of type I collagen. J.
Biol. Chem. 263,4624
-4628.
Johnson, K. J., Sage, H., Briscoe, G. and Erickson, H. P.
(1999). The compact conformation of fibronectin is determined by
intramolecular ionic interactions. J. Biol. Chem.
274,15473
-15479.
Jones, R. J., Avizienyte, E., Wyke, A. W., Owens, D. W., Brunton, V. G. and Frame, M. C. (2002). Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells. Br. J. Cancer 87,1128 -1135.[CrossRef][Medline]
Kaiura, T. L., Itoh, H. and Kent, K. C. (1999). The role of mitogen-activated protein kinase and protein kinase C in fibronectin production in human vascular smooth muscle cells. J. Surg. Res. 84,212 -217.[CrossRef][Medline]
Khan, M. Y., Medow, M. S. and Newman, S. A. (1990). Unfolding transitions of fibronectin and its domains. Stabilization and structural alteration of the N-terminal domain by heparin. Biochem. J. 270,33 -38.[Medline]
Klass, C. M., Couchman, J. R. and Woods, A.
(2000). Control of extracellular matrix assembly by syndecan-2
proteoglycan. J. Cell Sci.
113,493
-506.
Klinghoffer, R. A., Sachsenmaier, C., Cooper, J. A. and Soriano,
P. (1999). Src family kinases are required for integrin but
not PDGFR signal transduction. EMBO J.
18,2459
-2471.
Krammer, A., Lu, H., Isralewitz, B., Schulten, K. and Vogel,
V. (1999). Forced unfolding of the fibronectin type III
module reveals a tensile molecular recognition switch. Proc. Natl.
Acad. Sci. USA 96,1351
-1356.
Ladeda, V., Frankel, P., Feig, L. A., Foster, D. A., Bal de Kier Joffe, E. and Aguirre-Ghiso, J. A. (2001). RalA mediates v-Src, v-Ras, and v-Raf regulation of CD44 and fibronectin expression in NIH3T3 fibroblasts. Biochem. Biophys. Res. Commun. 283,854 -861.[CrossRef][Medline]
Langenbach, K. J. and Sottile, J. (1999).
Identification of protein-disulfide isomerase activity in fibronectin.
J. Biol. Chem. 274,7032
-7038.
Lee, B. H., Park, R. W., Choi, J. Y., Ryoo, H. M., Sohn, K. Y. and Kim, I. S. (1996). Stimulation of fibronectin synthesis through the protein kinase C signalling pathway in normal and transformed human lung fibroblasts. Biochem. Mol. Biol. Int. 39,895 -904.[Medline]
Lin, S., Sahai, A., Chugh, S. S., Pan, X., Wallner, E. I.,
Danesh, F. R., Lomasney, J. W. and Kanwar, Y. S.
(2002a). High glucose stimulates synthesis of fibronectin via a
novel protein kinase C, Rap1b, and B-Raf signaling pathway. J.
Biol. Chem. 277,41725
-41735.
Lin, W., Wang, S. M., Huang, T. F. and Fu, W. M. (2002b). Differential regulation of fibronectin fibrillogenesis by protein kinases A and C. Connect. Tissue Res. 43, 22-31.[Medline]
Litvinovich, S. V., Brew, S. A., Aota, S., Akiyama, S. K., Haudenschild, C. and Ingham, K. C. (1998). Formation of amyloid-like fibrils by self-association of a partially unfolded fibronectin type III module. J. Mol. Biol. 280,245 -258.[CrossRef][Medline]
Liu, B. P., Chrzanowska-Wodnicka, M. and Burridge, K. (1998). Microtubule depolymerization induces stress fibers, focal adhesions, and DNA synthesis via the GTP-binding protein Rho. Cell Adhes. Commun. 5,249 -255.[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.
McDonald, J. A., Quade, B. J., Broekelman, T. J., LaChance, R.,
Forsman, K., Hasegawa, E. and Akiyama, S. (1987).
Fibronectin's cell-adhesive domain and an amino-terminal matrix assembly
domain participate in its assembly into fibroblast pericellular matrix.
J. Biol. Chem. 262,2957
-2967.
McKeown-Longo, P. J. and Mosher, D. F. (1983). Binding of plasma fibronectin to cell layers of human skin fibroblasts. J. Cell Biol. 97,466 -472.[Abstract]
McKeown-Longo, P. J. and Mosher, D. F. (1985). Interaction of the 70,000-mol. wt. amino terminal fragment of fibronectin with matrix-assembly receptor of fibroblasts. J. Cell Biol. 100,364 -374.[Abstract]
Mercurius, K. O. and Morla, A. O. (2001). Cell adhesion and signaling on the fibronectin 1st type III repeat; requisite roles for cell surface proteoglycans and integrins. BMC Cell Biol. 2,18 .[CrossRef][Medline]
Midwood, K. S. and Schwarzbauer, J. E. (2002).
Tenascin-C modulates matrix contraction via focal adhesion kinase- and
Rho-mediated signaling pathways. Mol. Biol. Cell
13,3601
-3613.
Miranti, C. K. and Brugge, J. S. (2002). Sensing the environment: a historical perspective on integrin signal transduction. Nat. Cell Biol. 4, E83-E90.[CrossRef][Medline]
Morla, A., Zhang, Z. and Ruoslahtl, E. (1994). Superfibronectin is a functionally distinct form of fibronectin. Nature 367,193 -196.[CrossRef][Medline]
Mosher, D. F. (1993). Assembly of fibronectin into extracellular matrix. Curr. Opin. Struct. Biol. 3, 214-222.
Nagai, T., Yamakawa, N., Aota, S., Yamada, S. S., Akiyama, S. K., Olden, K. and Yamada, K. M. (1991). Monoclonal antibody characterizaion of two distant sites required for function of the central cell-binding domain of fibronectin in cell adhesion, cell migration, and matrix assembly. J. Cell Biol. 114,1295 -1305.[Abstract]
Oberhauser, A. F., Badilla-Fernandez, C., Carrion-Vazquez, M. and Fernandez, J. M. (2002). The mechanical hierarchies of fibronectin observed with single-molecule AFM. J. Mol. Biol. 319,433 -447.[CrossRef][Medline]
Oberhauser, A. F., Marszalek, P. E., Erickson, H. P. and Fernandez, J. M. (1998). The molecular elasticity of the extracellular matrix protein tenascin. Nature 393,181 -185.[CrossRef][Medline]
Oh, E. S., Woods, A. and Couchman, J. R.
(1997). Syndecan-4 proteoglycan regulates the distribution and
activity of protein kinase C. J. Biol. Chem.
272,8133
-8136.
Ohashi, T., Kiehart, D. P. and Erickson, H. P.
(1999). Dynamics and elasticity of the fibronectin matrix in
living cell culture visualized by fibronectin-green fluorescent protein.
Proc. Natl. Acad. Sci. USA
96,2153
-2158.
Ohashi, T., Kiehart, D. P. and Erickson, H. P.
(2002). Dual labeling of the fibronectin matrix and actin
cytoskeleton with green fluorescent protein variants. J. Cell
Sci. 115,1221
-1229.
Olden, K. and Yamada, K. M. (1977). Mechanism of the decrease in the major cell surface protein of chick embryo fibroblasts after transformation. Cell 11,957 -969.[Medline]
Olorundare, O. E., Peyruchaud, O., Albrecht, R. M. and Mosher,
D. F. (2001). Assembly of a fibronectin matrix by adherent
platelets stimulated by lysophosphatidic acid and other agonists.
Blood 98,117
-124.
Osusky, R., Soriano, D., Ye, J. and Ryan, S. J. (1994). Cytokine effect on fibronectin release by retinal pigment epithelial cells. Curr. Eye Res. 13,569 -574.[Medline]
Pankov, R., Cukierman, E., Katz, B. Z., Matsumoto, K., Lin, D.
C., Lin, S., Hahn, C. and Yamada, K. M. (2000).
Integrin dynamics and matrix assembly: tensin-dependent translocation of
alpha(5)beta(1) integrins promotes early fibronectin fibrillogenesis.
J. Cell Biol. 148,1075
-1090.
Pankov, R. and Yamada, K. M. (2002).
Fibronectin at a glance. J. Cell Sci.
115,3861
-3863.
Rief, M., Gautel, M., Oesterhelt, F., Fernandez, J. M. and Gaub,
H. E. (1997). Reversible unfolding of individual titin
immunoglobulin domains by AFM. Science
276,1109
-1112.
Rocco, M., Carson, M., Hantgan, R., McDonagh, J. and Hermans,
J. (1983). Dependence of the shape of the plasma fibronectin
molecule on solvent composition. J. Biol. Chem.
258,14545
-14549.
Ruoslahti, E. and Pierschbacher, M. D. (1987). New perspectives in cell adhesion: RGD and integrins. Science 238,491 -497.[Medline]
Saoncella, S., Echtermeyer, F., Denhez, F., Nowlen, J. K.,
Mosher, D. F., Robinson, S. D., Hynes, R. O. and Goetinck, P. F.
(1999). Syndecan-4 signals cooperatively with integrins in a
Rho-dependent manner in the assembly of focal adhesions and actin stress
fibers. Proc. Natl. Acad. Sci. USA
96,2805
-2810.
Schlaepfer, D. D., Hauck, C. R. and Sieg, D. J. (1999). Signaling through focal adhesion kinase. Prog. Biophys. Mol. Biol. 71,435 -478.[CrossRef][Medline]
Schwartz, M. A., Schaller, M. D. and Ginsberg, M. H. (1995). Integrins: Emerging paradigms of signal transduction. Annu. Rev. Cell Dev. Biol. 11,549 -599.[CrossRef][Medline]
Schwarzbauer, J. E. (1991). Identification of the fibronectin sequences required for assembly of a fibrillar matrix. J. Cell Biol. 113,1463 -1473.[Abstract]
Schwarzbauer, J. E., Paul, J. I. and Hynes, R. O. (1985). On the origin of species of fibronectin. Proc. Natl. Acad. Sci. USA 82,1424 -1428.[Abstract]
Schwarzbauer, J. E. and Sechler, J. L. (1999). Fibronectin fibrillogenesis: a paradigm for extracellular matrix assembly. Curr. Opin. Cell Biol. 11,622 -627.[CrossRef][Medline]
Sechler, J. L., Cumiskey, A. M., Gazzola, D. M. and
Schwarzbauer, J. E. (2000). A novel RGD-independent
fibronectin assembly pathway initiated by alpha4beta1 integrin binding to the
alternatively spliced V region. J. Cell Sci.
113,1491
-1498.
Sechler, J. L., Rao, H., Cumiskey, A. M., Vega-Colon, I., Smith,
M. S., Murata, T. and Schwarzbauer, J. E. (2001). A
novel fibronectin binding site required for fibronectin fibril growth during
matrix assembly. J. Cell Biol.
154,1081
-1088.
Sechler, J. L. and Schwarzbauer, J. E. (1997). Coordinated regulation of fibronectin fibril assembly and actin stress fiber formation. Cell Adhes. Commun. 4, 413-424.[Medline]
Sechler, J. L. and Schwarzbauer, J. E. (1998).
Control of cell cycle progression by fibronectin matrix architecture.
J. Biol. Chem. 273,25533
-25536.
Sechler, J. L., Takada, Y. and Schwarzbauer, J. E. (1996). Altered rate of fibronectin matrix assembly by deletion of the first type III repeats. J. Cell Biol. 134,573 -583.[Abstract]
Singh, L. P., Andy, J., Anyamale, V., Greene, K., Alexander, M.
and Crook, E. D. (2001). Hexosamine-induced
fibronectin protein synthesis in mesangial cells is associated with increases
in cAMP responsive element binding (CREB) phosphorylation and nuclear CREB:
the involvement of protein kinases A and C. Diabetes
50,2355
-2362.
Somers, C. E. and Mosher, D. F. (1993). Protein
kinase C modulation of fibronectin matrix assembly. J. Biol.
Chem. 268,22277
-22280.
Sottile, J. and Mosher, D. F. (1993). Assembly of fibronectin molecules with mutations or deletions of the carboxyl-terminal type I modules. Biochemistry 32,1641 -1647.[Medline]
Sottile, J. and Mosher, D. F. (1997). N-terminal type I modules required for fibronectin binding to fibroblasts and to fibronectin's III1 module. Biochem. J. 323, 51-60.[Medline]
Sottile, J., Schwarzbauer, J., Selegue, J. and Mosher, D. F.
(1991). Five type I modules of fibronectin form a functional unit
that binds to fibroblasts and Staphylococcus aureus. J. Biol.
Chem. 266,12840
-12843.
Ugarova, T. P., Ljubimov, A. V., Deng, L. and Plow, E. F. (1996). Proteolysis regulates exposure of the IIICS-1 adhesive sequence in plasma fibronectin. Biochemistry 35,10913 -10921.[CrossRef][Medline]
Ugarova, T. P., Zamarron, C., Veklich, Y., Bowditch, R. D., Ginsberg, M. H., Weisel, J. W. and Plow, E. F. (1995). Conformational transitions in the cell binding domain of fibronectin. Biochemistry 34,4457 -4466.[Medline]
Vuori, K. and Ruoslahti, E. (1993). Activation
of protein kinase C precedes alpha 5 beta 1 integrin-mediated cell spreading
on fibronectin. J. Biol. Chem.
268,21459
-21462.
Wennerberg, K., Lohikangas, L., Gullberg, D., Pfaff, M., Johansson, S. and Fassler, R. (1996). ß1 integrin-dependent and -independent polymerization of fibronectin. J. Cell Biol. 132,227 -238.[Abstract]
Wierzbicka-Patynowski, I. and Schwarzbauer, J. E.
(2002). Regulatory role for Src and phosphatidylinositol 3-kinase
in initiation of fibronectin matrix assembly. J. Biol.
Chem. 277,19703
-19708.
Wilcox-Adelman, S. A., Denhez, F. and Goetinck, P. F.
(2002). Syndecan-4modulates focal adhesion kinase
phosphorylation. J. Biol. Chem.
277,32970
-32977.
Williams, E. C., Janmey, P. A., Ferry, J. D. and Mosher, D.
F. (1982). Conformational states of fibronectin. Effects of
pH, ionic strength, and collagen-binding. J. Biol.
Chem. 257,14973
-14978.
Woods, A., Johansson, S. and Hook, M. (1988). Fibronectin fibril formation involves cell interactions with two fibronectin domains. Exp. Cell Res. 177,272 -283.[Medline]
Wu, C., Hughes, P. E., Ginsberg, M. H. and McDonald, J. A.
(1996). Identification of a new biological function for the
integrin vß3: Initiation of fibronectin matrix assembly.
Cell Adhes. Commun. 4,149
-158.[Medline]
Wu, C., Keivens, V. M., O'Toole, T. E., McDonald, J. A. and Ginsberg, M. H. (1995). Integrin activation and cytoskeletal interaction are essential for the assembly of a fibronectin matrix. Cell 83,715 -724.[Medline]
Yang, R. S., Tang, C. H., Ling, Q. D., Liu, S. H. and Fu, W.
M. (2002). Regulation of fibronectin fibrillogenesis by
protein kinases in cultured rat osteoblasts. Mol.
Pharmacol. 61,1163
-1173.
Yi, M. and Ruoslahti, E. (2001). A fibronectin
fragment inhibits tumor growth, angiogenesis, and metastasis. Proc.
Natl. Acad. Sci. USA 98,620
-624.
Zamir, E., Katz, B. Z., Aota, S., Yamada, K. M., Geiger, B. and
Kam, Z. (1999). Molecular diversity of cell-matrix adhesions.
J. Cell Sci. 112,1655
-1669.
Zamir, E., Katz, M., Posen, Y., Erez, N., Yamada, K. M., Katz, B. Z., Lin, S., Lin, D. C., Bershadsky, A., Kam, Z. et al. (2000). Dynamics and segregation of cell-matrix adhesions in cultured fibroblasts. Nat. Cell Biol. 2, 191-196.[CrossRef][Medline]
Zhang, Q., Checovich, W. J., Peters, D. M., Albrecht, R. M. and Mosher, D. F. (1994). Modulation of cell surface fibronectin assembly sites by lysophosphatidic acid. J. Cell Biol. 127,1447 -1459.[Abstract]
Zhang, Q., Magnusson, M. K. and Mosher, D. F. (1997). Lysophosphatidic acid and microtubule-destabilizing agents stimulate fibronectin matrix assembly through Rho-dependent actin stress fiber formation and cell contraction. Mol. Biol. Cell 8,1415 -1425.[Abstract]
Zhao, J. H. and Guan, J. L. (2000). Role of focal adhesion kinase in signaling by the extracellular matrix. Prog. Mol. Subcell. Biol. 25, 37-55.[Medline]
Zhong, C., Chrzanowska-Wodnicka, M., Brown, J., Shaub, A.,
Belkin, A. M. and Burridge, K. (1998). Rho-mediated
contractility exposes a cryptic site in fibronectin and induces fibronectin
matrix assembly. J. Cell Biol.
141,539
-551.
Related articles in JCS: