Fibronectin-binding integrins in cell
integrins such as
alpha-V/beta-3 can promote different aspects of cell
migration. Adhesion to fibronectin by
alpha-V/beta-3 integrins supports persistent migration,
whereas alpha-5/beta-1 integrins promote random migration
Integrin clustering induces focal adhesion kinase
(FAK1) autophosphorylation, which creates a binding site for
the proto-oncogene tyrosine-protein kinase Src (c-Src).
c-Src-mediated phosphorylation of
FAK1 promotes its maximal catalytic activity. The
integrin-binding protein talin
recruits FAK1 and vinculin to
focal contacts. Alpha-actinin is a cytoskeletal protein that
binds to vinculin and crosslinks
actin in actomyosin stress fibres and tethers them to the
focal contacts. Phosphorylation of alpha-actinin by
FAK1 reduces the crosslinking
of stress fibres and prevents the maturation of focal contacts .
Vinculin transiently recruits the actin-related protein
complex Arp2/3 to new sites of
integrin aggregation .
Arp2/3 complex nucleates new
actin filaments from the sides of preexisting filaments.
This interaction requires phosphorylation of Arp2/3 complex
by PAK1 (p21-activated kinase 1), which promotes
actin polymerization , .
FAK1 plays a key role in the control of focal adhesion
dynamics and cell migration under the regulation of small GTPases of Rho family
(Rac1, Cdc42 and
Rho-A) , . RhoA downstream effector
ROCK (protein Rho-associated kinase) directly phosphorylates
LIMK1 and LIMK2 (LIM-kinases),
which in turn phosphorylate cofilin (actin-associated
protein). Cofilin exhibits
actin-depolymerizing activity followed by reorganization of
the actin cytoskeleton .
Activity of LIMK1 is also regulated by
PAK1, the downstream effector of
Rac1 and Cdc42 . Cdc42 effector
N-WASP (a homolog to the Wiskott-Aldrich syndrome protein)
 regulates actin polymerization by stimulating the
actin-nucleating activity of the
Arp2/3 complex .
The Arp2/3 complex and cofilin
are involved in the generation of propulsive force at the leading edge:
the severing activity of cofilin and the branching activity
of Arp2/3 act in synergy to drive the extension of
lamellipodia. Cofilin is also required for the maintenance
of a polarized cytoskeleton and thus for directional cell migration .
It was shown that the persistent mode of migration of cells bound to
fibronectin by alpha-V/beta-3
integrins is associated with relatively high levels of
cofilin activity and low levels of
RhoA activity. Adhesion by
alpha-5/beta-1 instead stimulates an increase in
of cofilin and supports random cell migration
Integrin signaling is mediated by distinct and separable
interactions of the integrin
beta tails. c-Src was shown to
bind constitutively and selectively to beta3 integrins
. c-Src could, in turn, phosphorylate and
stimulate GTPase-activating protein (GAP) p190 RhoGAP. The
GAP activity of RhoGAP is specific for
RhoA inhibition .
Vav1, a guanine nucleotide exchange factor for
Rac1, Cdc42 and
Rho-A, that stimulates the
exchange of bound GDP for GTP, was shown to stimulate
preferentially Rac1 and RhoA
under integrin alpha-v/beta-3-mediated adhesion of
hematopoietic cells, but this effect was investigated on vitronectin substrate .
Tyrosine kinase Fyn could phosphorylate and activate
Caveolin-1 was shown to function as a membrane adaptor to
link the integrin alpha-5 or
alpha-v subunit to the Fyn
. Vav1 activity is directly controlled by
substrates and products of phosphatidylinositol 3-kinase
(PI(4,5)P2) inhibits activation of
Vav1, whereas the product
enhances phosphorylation and activation of Vav1 . FAK1 activation may lead to its association with
the regulatory subunit of PI3K (PI3K reg
p85), which can subsequently activate PI3K
during cell adhesion , . PI3K reg p85
associate with Vav1 in some
types of cells .
The protein Nischarin was found to bind preferentially to
the cytoplasmic tail of the integrin alpha-5 subunit and to
inhibit cell migration . Nischarin was not
found in focal adhesion sites, suggesting that it binds to integrins
when they are not ligated by the proteins of the extracellular matrix.
Once the integrins enter into
adhesion sites, Nischarin is released, allowing it to bind
to the activated PAK1. This binding is enhanced by active
Rac1. Interaction with
Nischarin strongly inhibits the ability of
PAK1 to phosphorylate substrates and this effect closely
parallels Nischarin's ability to inhibit cell motility
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