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How do cells move?
Cell motility has been studied extensively in cultured fibroblasts. Few
embryonic cells are as amenable to investigation as are cells in culture.
The deep cells of the fish blastula are an exception. The fish embryo is
transparent, and the behaviors of individual cells can be tracked. They
have been studied most extensively by Dr. J.P. Trinkaus. These studies have
revealed that the fibroblast model provides a good approximation of embryonic
Cell motility is generated by contractile elements of the cytoskeleton.
It is unfortunate that the term "cytoskeleton" implies rigidity,
because the cytoskeleton is dynamic.
Microfilaments play key roles in generation of motility. Microfilaments
are organized in one of two ways in fibroblasts. Microfilaments form a meshwork
in the leading edge (lamellipodium), whereas transient bundles of microfilaments
(stress bundles) extend along the length of cells.
(See Browder et al., 1991, Figs. 9.17, 9.18A; Gilbert, 1997,
The bundles of microfilaments are attached to focal contacts,
which anchor the bundles to the plasma membrane. Focal contacts facilitate
attachment of the cell to the substratum, and allow cells to exert tension
on the substratum, which is necessary for cell migration along the substratum.
(See Browder et al., 1991, Fig. 9.8; Shostak, 1991, Fig. 20.6;
Wolpert et al., Box 8B)
There are three major processes in fibroblast motility (Alberts et
al., 1994; see Fig. 16-80):
Protrusion of lamellipodia or filopodia, which is thought to be due
to actin polymerization at the leading edge. Other possible mechanisms for
generating the force of extension include a local increase in osmotic pressure,
an increase in hydrostatic pressure caused by contraction of the cortex
elsewhere in the cell or, alternatively, myosin-I motors attached to the
plasma membrane that would drive the cell forward by walking along the actin
(See Browder et al., Fig. 9.5; Gilbert, 1997, Fig. 6.3; Kalthoff,
1996, Figs. 2.18, 2.19, 2.20; Wolpert et al., Fig. 8.33)
Formation of focal contacts, which anchor the lamellipodium in its new
position, permitting net forward progress.
Retraction of the trailing edge. This retraction involves both contraction
of the cytoskeleton and passive recoil due to the elasticity of the cytoskeleton
and plasma membrane.
(See Browder et al., Fig. 9.6)
The main molecules that mediate cell anchorage to the substratum are members
of a family of transmembrane linker proteins known as integrins.
Integrins traverse the cell membrane, anchoring the actin microfilaments
on the inside and binding to the fibronectin of the extracellular
(See Alberts et al., 1994, Fig. 16-75)
Linkage of integrin to the microfilaments is indirect and involves a
number of attachment proteins. The cytoplasmic domain of integrin binds
to talin, which binds to vinculin, which binds to alpha-actinin, which binds
to actin filaments. Each integrin molecule is a dimer of alpha and beta
subunits. There is a diversity of alpha and beta integrins (over 24 members
of the integrin family are known); different combinations of alpha and beta
subunits provide different cell types with different affinities for the
extracellular matrix. For example, alpha2 beta1 binds to collagen and laminin,
whereas alpha4 beta1 binds to fibronectin (Gilbert, 1997).
The significance of integrins during development is demonstrated by mutations
of genes encoding integrins in Drosophila, which either cause developmental
abnormalities or death. A number of correlations have been drawn between
changes in the expression of integrins and developmental processes. For
example, a single layer of keratinocytes gives rise to mature human epidermal
tissue through a process of stratification, which is associated with changes
is the types and locations of integrin expression. During muscle development,
the fusion of individual myoblasts to form myotubes is a key step in the
differentiation process. Fusion is correlated with a change in the expression
of ß1 integrins on the surface of the cells. (For a review of integrins
in development, see Adams and Watt, 1993.)
One of the most prevalent components of the extracellular matrix is fibronectin.
All known cellular receptors for fibronectin belong to the integrin family.
The significance of the fibronectin/integrin interaction is exemplified
by knockouts of the genes encoding either fibronectin or two fibronectin
receptors (integrins alpha4 and alpha5) in mice, which cause developmental
defects that are severe enough to cause embryonic lethality (George et
al., 1993; Yang et al., 1993, 1995). Fibronectin molecules are
dimers having domains with distinct binding properties. One domain binds
to collagen, one binds to heparin and another binds to cell surfaces. The
cell surface binding domain is characterized by the presence of an essential
Arg-Gly-Asp (RGD) tripeptide. The RGD sequence is so critical for binding
that short peptides having the RGD sequence will compete with fibronectin
for binding and inhibit the attachment of cells to a fibronectin matrix.
The RGD sequence is also found in other extracellular matrix (ECM) proteins.
The RGD sequence is recognized by members of the integrin family, although
it is not sufficient to account for the specificity of binding between integrins
and ECM molecules; other regions of the molecule must provide that specificity.
(See Alberts et al., Fig. 19-51)
In addition to their roles in fibroblasts, integrins are expressed in epithelial
cells. In fact, virtually every cell type of multicellular organisms expresses
integrins, mediating their interactions with the extracellular matrix. Integrins
not only play a structural role; they are also involved in communicating
signals from the extracellular matrix into the cell. The clustering of integrins
at the sites of contact with the matrix can activate several intracellular
signaling pathways. The signals that the integrins initiate appear to influence
such cell properties as differentiation, proliferation, survival, and gene
expression (Sheppard, 1996).
The cytoplasmic domains of the integrin subunits have no intrinsic enzymatic
activity. Thus, they do not function like kinase enzymes that pass a signal
on to a receptor molecule by phosphorylating it. Instead, they function
by initiating the assembly of a functional signaling complex that contains
catalytic signaling proteins, such as protein kinases (Clark and Brugge,
Control of Directional Migration
To study this topic, you should go to The
Molecular Basis of Migratory Specificity in Zygote.
- What are focal contacts?
- What is thought to be responsible for protrusion of lamellipodia?
- What are the functions of integrins?
- What are the properties of integrins?
- How has the significance of integrins been demonstrated in Drosophila
- Discuss the interactions between integrins and fibronectin and describe
an experiment to demonstrate the significance of these interactions.
- Define the following phenomena and give an example of each phenomenon:
contact inhibition of movement
Link to Related Material
of Thin Filopodia
Chen, C.S., Mrsich, M., Huang, S., Whitesides, G.M. and Ingber, D.E.
1997. Geometric control of cell life and death. Science 276: 1425-1428..
Ruoslahti, E. 1997. Stretching is good for a cell. Science 276: 1345-1346.
Wallingford, J.B., Sater, A.K., Uzman, J.A. and Danilchik, M.V. 1997. Inhibition
of morphogenetic movement during Xenopus gastrulation by injected
sulfatase: implications for anteroposterior and dorsoventral axis formation.
Develop. Biol. 187: 224-235.
Zipkin, I.D., Kindt, R.M. and Kenyon, C.J. 1997. Role of a new Rho family
member in cell migration and axon guidance in C. elegans. Cell 90: 883-894.
Adams, J.C. and Watt, F.M. 1993. Regulation of development and differentiation
by the extracellular matrix. Development 117: 1183-1198.
Alberts, B. et al. 1994. Molecular Biology of the Cell. Third
edition. Garland. New York.
Browder, L.W., Erickson, C.A. and Jeffery, W.R. 1991. Developmental Biology.
Third edition. Saunders College Pub. Philadelphia.
Clark, E.A. and J.S. Brugge. 1995. Integrins and signal transduction pathways:
the road taken. Science 268: 233-239.
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.
Gilbert, S.F. 1997. Developmental Biology. Fifth edition. Sinauer.
Kalthoff, K. 1996. Analysis of Biological Development. McGraw-Hill.
Sheppard, D. Epithelial integrins. BioEssays 18: 655-660.
Shostak, S. 1991. Embryology. An Introduction to Developmental Biology.
HarperCollins. New York.
Wolpert, L., Beddington, R., Brockes, J., Jessell, T., Lawrence, P. and
Meyerowitz, E. 1998. Principles of Development. Current Biology.
Yang, J.T., Rayburn, H. and Hynes, R.O. 1993. Embryonic mesodermal defects
in alpha 5 integrin-deficient mice. Development 119: 1093-1105.
Yang, J.T., Rayburn, H. and Hynes, R.O. 1995. Cell adhesion events mediated
by alpha 4 integrins are essential in placental and cardiac development.
Development 121: 549-560.