Integrin outside-in signaling
Integrins are heterodimeric adhesion receptors composed
of alpha- and beta-subunits. It is known that at least 18 distinct alpha subunits and 8
or more beta subunits lead to generation of 24 alpha/beta heterodimeric receptors. Most
integrins recognize extracellular matrix (ECM) proteins, such as
Vitronectin and Collagen
(types I, II and IV) .
Unstimulated cells are non-adherent, and cell adhesion to ECM can alter integrin
avidity through intracellular signaling (inside-out signaling).
Talin binding to Integrin beta subunit triggers
conformational changes of Integrins, increasing their
affinity to the ECM proteins .
Cell adhesion to ECMs can activate diverse intracellular kinases, including
tyrosine-protein kinase c-Src, focal adhesion kinase
FAK1 and integrin-linked protein kinase
FAK1 is autophosphorylated in response to integrin
activation, and/or is phosphorylated by c-Src leading to
enhancement of catalytic activity of FAK1 .
Integrin binding of FAK1 is not
required for FAK1 localization to the focal adhesions. This
may be due to the fact that FAK1 binds to
Talin and Paxillin, which
interacts with Integrins , .
A major function of integrin signaling is to link ECM proteins to intracellular actin
filaments via interactions of integrins with actin-binding proteins such as
Filamin A, Talin,
Alpha-actinin and ILK/
(alpha- and/or beta-) complex
Filamin A links actin filaments in orthogonal networks or
parallel bundles, and can induce reorganization of the cytoskeleton by different
pathways. Filamin A recruits a guanine nucleotide exchange
factor (GEF) TRIO, which catalyses the transition of
Filamin-bound Ras-like protein
Rac1 from the GDP bound to the
the GTP form . Rac1-GTP then activates
p21-activated kinase 1 (PAK1). Alternatively,
Filamin A directly associates with and activated
PAK1, leading to PAK-induced
phosphorylation of Filamin A .
PAK1 also promotes activation of
Actin polymerization by phosphorylating of
Arp2/3 (complex of actin-related proteins) , .
Talin is also important for the linkage of integrins to
the cytoskeleton. Upon integrin clustering Talin is
recruited to focal complexes where it binds and activates phosphatidylinositol phosphate
kinase type 1 gamma (PIPKI gamma), that leads to the
production of phosphatidylinositol-4,5-bisphosphate
PtdIns(4,5)P2 binds to Talin
and increases its interaction with Integrin.
PtdIns(4,5)P2 also binds to
Vinculin, which then interacts with
Vinculin is replaced by Actin filaments.
vinculin can transiently bind to the
Arp2/3 complex, which nucleates
Actin polymerization. This interaction also requires
Rac1 activation leading
to Arp2/3 phosphorylation by
Alpha-actinin connects actin
fibrils to the cytoplasmic tail of integrins
and crosslinks actin filaments to actin
bundles and networks. PtdIns(4,5)P2 binding
to Alpha-actinin increases its interaction with
Actin . Phosphorylation of
Alpha-actinin by FAK1 decreases its
associating with Actin.
Alpha-actinin can also connect to Actin
filaments via its interaction with Vinculin
ILK binds to beta Integrin
subunits and phosphorylates AKT(PKB) kinase, leading to
integrin-mediated cell proliferation and survival. Another ILK
target is GSK-3 beta, whose phosphorylation
leads to stabilization and increase of Beta-catenin in
nucleus where it associates with transcription factors
Tcf/Lef-1 to activate gene expression including
c-Myc and Cyclin D1 .
ILK was shown to bind adapter protein PINCH
which interacts with adapter protein
NCK2(Grb4) , , . NCK2(Grb4) can recruit
PAK1 and WASP (Wiskott-Aldrich
Sydrome protein) interacting protein WIRE, leading
to Arp2/3 activation
and Actin polymerization , .
Cell adhesion to extracellular matrix also regulates cell proliferation and survival.
Integrin activation by Fibronectin induces phosphorylation
of FAK1 and Paxillin and causes
the formation of FAK1/ GRB-2/
SOS complexes, leading to
MEK1, MEK2/ Erk (MAPK1/3)
ILK can recruit a family of F-actin binding proteins
including Alpha-parvin and
Beta-parvin. Formation of ILK/
PINCH/ Parvin complex is
essential but not sufficient for cell adhesion .
Paxillin is an additional interactor, which binds
Alpha-parvin to focal adhesions via interaction with
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