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News and Publications
Signal Transduction by Integrins
M.A. Schwartz, M. del Pozo, A. Katsumi, W.B. Kiosses, J.M.
Lewis, N. Meller, J. Milanini, G.R. Schlunck, N.R. Schofield, E.
Tzima
In addition to its structural role in tissue organization and
cell adhesion, the extracellular matrix regulates many important
cell functions, including growth, cytoskeletal organization, survival,
and gene expression. Transduction of signals across the plasma membrane
by integrins appears to account for many of these regulatory effects.
These functions are also controlled by soluble hormones and growth
factors and by mechanical signals. Our research is directed toward
understanding how cells integrate signals from soluble factors,
integrin-mediated adhesion to proteins in the extracellular matrix,
and mechanical forces.
A major area of interest is the involvement of the small GTPases
Rho, Cdc42, and Rac in integrin signal transduction. Rac mediates
formation of lamellipodia and is critical in cell migration. Rac
is also activated by integrins and promotes spreading of cells when
the cells are plated on fibronectin or other proteins of the extracellular
matrix. Additionally, integrins play an unexpected but critical
role in the function of Rac when this GTPase is activated by growth
factors. Although growth factors still trigger Rac activation in
nonadherent cells, the activated protein does not translocate to
the plasma membrane and does not bind to its effectors.
In collaboration with K. Hahn, Department of Cell Biology, we
recently reported that this effect on Rac membrane targeting is
local, so that Rac translocates to regions of the plasma membrane
near occupied integrins. Rac in the cytoplasm is bound to the regulatory
protein Rho GDP-dissociation inhibitor (GDI), a chaperone protein
that makes Rac soluble in aqueous media. We also found that Rho
GDI blocks effector binding to Rac so that membrane translocation
promotes local effector interaction by dissociating Rho GDI. We
are investigating the mechanism of this effect and its consequences
for cell growth, cell migration, and malignant transformation. We
also showed that the Rac effector p21-activated kinase regulates
cytoskeletal organization, migration, and angiogenesis in endothelial
cells.
Most upstream activators of Rho family GTPases are guanine nucleotide
exchange factors related to the dbl family of nucleotide exchange
factors. We cloned a novel Cdc42-activating protein that interacts
directly with Cdc42 that is not related to dbl. Instead, it has
homology to DOCK180, a protein known to activate Rac. These results
define a new family of guanine nucleotide exchange factors for Rho
family proteins.
Our interest in integrins and Rho family GTPases led us into the
field of mechanotransduction. The responses of cells to mechanical
forces, for example, being stretched on an elastic substratum or
being exposed to fluid shear stress (i.e., flow), play important
roles in vascular morphogenesis and pathologic changes. We elucidated
a pathway that defines a surprising role for integrins in the responses
of endothelial cells to fluid shear stress. We found that shear
triggers rapid conversion of integrins to a high-affinity state,
leading to new binding to proteins in the extracellular matrix.
Newly occupied integrins then initiate signals that induce adaptation
to flow. These signals include the small GTPases Rho and Rac. Both
of these GTPases must be properly regulated for endothelial cells
to align in the direction of flow. Rac is also required for flow-induced
activation of the transcription factor NF-*B and subsequent gene
expression. In further studies, we will investigate how integrins
are activated and the role of these integrin-dependent signals in
atherogenesis.
Studies in mechanotransduction include investigations of the effects
of stretch. When cells on elastic membranes are stretched, Rac is
inactivated, leading to inhibition of membrane ruffling. When stretched
in one dimension, Rac is inhibited at the cell edges parallel to
stretch, whereas edges perpendicular to the direction of stretch
have no lamellipodia. Tension generated by endogenous actin and
myosin also appears to inhibit Rac at cell edges parallel to the
actin stress fibers.
Finally, we are studying the role of integrins in cellular responses
to DNA damage. Radiation and chemotherapy cause DNA damage to selectively
kill cancer cells. However, in many instances, small numbers of
cancer cells survive and cause recurrence of therapy-resistant tumors.
We found that loss of adhesion, as might occur for an invasive or
metastatic cancer cell, results in resistance to DNA damage and
accumulation of mutations that could favor progression to resistance.
Antibodies to integrins reverse this effect. The loss of sensitivity
to DNA damage is mediated by decreased levels of p53. We are investigating
the mechanism of this effect and its relevance to cancer therapy
in vivo.
PUBLICATIONS
Calderwood, D.A., Huttenlocher, A., Kiosses, W.B., Rose, D.M.,
Woodside, D.G., Schwartz, M.A., Ginsberg, M.H. Increased filamin
binding to b integrin
cytoplasmic domains inhibits cell migration. Nat. Cell Biol. 3:1060,
2001.
del Pozo, M.A., Kiosses, W.B., Alderson, N.B., Meller, N.,
Hahn, K.M., Schwartz, M.A. Integrins regulate GTP-Rac localized
effector interactions through dissociation of Rho-GDI. Nat. Cell
Biol. 4:232, 2002.
Jalali, S., del Pozo, M.A., Chen, K., Miao, H., Li, Y., Schwartz,
M.A., Shyy, J.Y.-J., Chien, S. Integrin-mediated mechanotransduction
requires its dynamic interaction with specific extracellular matrix
(ECM) ligands. Proc. Natl. Acad. Sci. U. S. A. 98:1042, 2001.
Kiosses, W.B., Hood, J., Yang, S., Gerritsen, M.E., Cheresh,
D.A., Alderson, N., Schwartz, M.A. A dominant negative p65 PAK
peptide inhibits angiogenesis. Circ. Res. 90:697, 2002.
Lewis, J.M., Truong, T.N., Schwartz, M.A. Integrins regulate
the apoptotic response to DNA damage through modulation of p53.
Proc. Natl. Acad. Sci. U. S. A. 99:3627, 2002.
Obergfell, A., Judd, B.A., del Pozo, M.A., Schwartz, M.A.,
Koretzky, G.A., Shattil, S.J. The molecular adapter SLP-76 relays
signals from platelet integrin aIIbb3
to the actin cytoskeleton. J. Biol. Chem. 276:5916, 2001.
Schwartz, M.A., Assoian, R.K. Integrins and cell proliferation:
regulation of cyclin-dependent kinases via cytoplasmic signaling
pathways. J. Cell Sci. 114:2553, 2001.
Schwartz, M.A., Ginsberg, M.H. Networks and cross talk:
integrin signaling spreads. Nat. Cell Biol. 4:E65, 2002.
Sun, J., Zhao, J., Schwartz, M.A., Wang, J.Y., Weidmer, T.,
Sims, P.J. c-Abl tyrosine kinase binds and phosphorylates phospholipid
scramblase 1. J. Biol. Chem. 276:28984, 2001.
Welsh, C.F., Roovers, K., Villanueva, J., Liu, Y., Schwartz,
M.A., Assoian, R.K. Timing of cyclin D1 expression within G1
phase is controlled by Rho. Nat. Cell Biol. 3:950, 2001.
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