Department of Microbiology, Box 800734, University of Virginia Health System, Charlottesville, VA 22908, USA
e-mail: jtp{at}virginia.edu
![]() |
Summary |
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Key words: Kinase, Focal Adhesion, Migration, Cytoskeleton
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Introduction |
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![]() |
The structure of FAK clues to function |
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|
FAK comprises a central catalytic domain flanked by large N- and C-terminal
non-catalytic domains (Fig. 1).
The N-terminal domain exhibits sequence similarity to a family of proteins
containing so-called FERM (erythrocyte band four.1-ezrin-radixin-moesin)
domains (Girault et al., 1999;
Sun et al., 2002
). In general,
members of this family link transmembrane glycoproteins to the actin
cytoskeleton. In the case of FAK, the role of the FERM domain is unclear. In
vitro, the N-terminal domain of FAK binds to sequences in the cytoplasmic
domain of ß-integrin subunits
(Schaller et al., 1995
),
although a demonstration of a direct interaction between FAK and integrin
receptors in vivo is still lacking. Interestingly, recent evidence indicates
that the FERM domain of the adhesion protein talin binds to ß3 integrin
tails and regulates integrin activation
(Calderwood et al., 1999
). The
N-terminal domain also mediates interaction with activated forms of the
epidermal growth factor (EGF) receptor, although it is not clear whether these
interactions are direct (Sieg et al.,
2000
). Recently, studies on Etk/BMX, a member of the Btk family of
tyrosine kinases, have shown that the activation of Etk by extracellular
matrix proteins is regulated by FAK and requires an interaction between the PH
domain of Etk and the FERM domain of FAK (Chen, 1994). Additional evidence
supports a role for the FERM domain in regulating catalytic activity and
subcellular localization (Dunty and
Schaller, 2002
; Stewart et
al., 2002
). Thus, the N-terminal FERM domain may direct FAK to
sites of integrin or growth factor receptor clustering as well as regulating
its interactions with other potential activating proteins.
The C-terminal region of FAK is rich in protein-protein interaction sites.
An 100 residue sequence designated `FAT' for focal adhesion targeting
(Fig. 1) directs FAK to newly
formed and existing adhesion complexes
(Martin et al., 2002
).
Sequences within this domain are both necessary and sufficient to target FAK
to adhesion complexes (Hildebrand et al.,
1993
), and the integrity of this region is essential for FAK
signaling (Sieg et al., 1999
;
Thomas et al., 1999
)
(Fig. 1). Both X-ray
crystallography and NMR analysis of the FAT domain reveal a four-helix bundle
that resembles structures present in other adhesion proteins, including
vinculin, Cas and
-catenin (Arold et
al., 2002
; Hayashi et al.,
2002
; Liu, G. et al.,
2002
). The FAT domain is also the binding site for the focal
adhesion protein paxillin. This interaction requires the structural integrity
of the helical bundle and is mediated by two hydrophobic `patches' on opposite
faces of the bundle. These `patches' are proposed to bind to two `LD' motifs
on paxillin (Arold et al.,
2002
; Hayashi et al.,
2002
; Liu, G. et al.,
2002
). Because paxillin binds directly to the cytoplasmic domains
of integrin receptors (Liu et al.,
1999
; Schaller et al.,
1995
), as well as to the focal adhesion protein vinculin, paxillin
may function as the `docking partner' for FAK in adhesion complexes.
Interestingly, certain FAK variants that fail to bind paxillin in vitro are
still targeted to adhesions in vivo
(Hildebrand et al., 1995
).
Thus the mechanism for FAK recruitment to adhesion structures may require more
than simple paxillin binding.
The C-terminal, non-catalytic domains of both FAK and PYK2, termed FRNK
(FAK-related-non-kinase) and PRNK (PYK2 related non-kinase), respectively, are
expressed independently in certain cells and may function as negative
regulators of kinase activity (Schaller et
al., 1993; Taylor et al.,
2001
; Xiong and Parsons,
1997
). In the case of FRNK, expression is controlled by
transcriptional elements residing between the 3'-most exon of the kinase
domain and the first exon of the C-terminal domain
(Nolan et al., 1999
). FRNK
expression is elevated in vascular smooth muscle cells and appears to be
upregulated in response to vascular injury
(Taylor et al., 2001
). In most
cells, forced overexpression of FRNK inhibits cell spreading, cell migration
and growth-factor-mediated signals to MAP kinase
(Hauck et al., 2001
;
Richardson et al., 1997
;
Taylor et al., 2001
).
The kinase domain of FAK shares sequence similarity with other receptor and
non-receptor protein tyrosine kinases. Interestingly the crystal structure of
the FAK kinase domain reveals the presence of a disulphide bond in the
N-terminal lobe of the kinase. This is an unusual feature for kinases and
suggests a possible role in kinase function
(Nowakowski et al., 2002).
Clustering of integrins results in rapid phosphorylation of FAK at Tyr397, as
well as at several additional sites within the kinase and C-terminal domains
(Calalb et al., 1995
). Recent
evidence indicates that transient dimerization of FAK molecules leads to
intermolecular phosphorylation of Tyr397
(Toutant et al., 2002
).
Phosphorylation at Tyr397 correlates with increased catalytic activity of FAK
(Calalb et al., 1995
;
Lipfert et al., 1992
) and
appears to be important for tyrosine phosphorylation of
focal-adhesion-associated proteins (Cobb
et al., 1994
; Schaller et al.,
1999
; Schaller et al.,
1994
) (Fig. 2) as
well as phosphorylation at Tyr576 and Tyr577, two highly conserved residues
positioned within the `catalytic loop' of the kinase domain
(Owen et al., 1999
).
Phosphorylation of these tyrosine residues is important for the maximal
adhesion-induced activation of FAK and signaling to downstream effectors
(Calalb et al., 1995
;
Owen et al., 1999
).
|
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FAK as a `switch' for multiple signaling outputs |
---|
FAK contains four sites of serine phosphorylation within the C-terminal
domain (Ser722, Ser843 and Ser846, and Ser910). The role of serine
phosphorylation in the regulation of FAK function is poorly understood;
however, the proximity of several of these phosphorylated serine residues to
sites of protein-protein interaction is provocative
(Ma et al., 2001) and suggests
a role for serine phosphorylation in modulating binding/stability of
downstream signaling proteins.
The C-terminal domain harbors multiple protein-protein interactions sites.
In addition to the paxillin-binding site in the FAT domains, two additional
sites contain proline-rich recognition sites for SH3-domain-containing
proteins (site I and site II, Fig.
1). Site I provides the major binding motif recognized by the SH3
domain of Cas, a multi-functional adapter protein
(Harte et al., 1996;
O'Neill et al., 2000
;
Polte and Hanks, 1995
). Upon
integrin clustering, Cas is localized to adhesion complexes and is
phosphorylated on tyrosine (Harte et al.,
1996
; O'Neill et al.,
2000
; Petch et al.,
1995
; Polte and Hanks,
1995
). FAK mutants that lack the binding site for Cas exhibit
compromised signaling to downstream effectors (see below). The site II motif
binds the SH3 domains of two regulators of small GTPases: GRAF, a GAP
(GTPase-activating protein) for Rho; and ASAP1, a GAP for Arf 1 and Arf 6 (Liu
et al., 2002b; Randazzo et al.,
2000
; Taylor et al.,
1998
; Taylor et al.,
1999
). Interestingly, neither GRAF nor ASAP appears to be
efficiently tyrosine phosphorylated in either the bound or unbound state (Liu,
Y., 2002; Taylor et al.,
1998
). In addition, whereas the expression of GRAF is cell type
specific, interactions between FAK and ASAP appear to be common to many cell
types (Liu, Y., 2002). Thus the binding of ASAP and/or GRAF to FAK appears
important to link adhesion complex signaling with the concerted regulation of
small GTP-binding proteins in the Rho and Arf families, proteins that clearly
play an important function in cytoskeletal reorganization.
The interaction of FAK with multiple binding partners raises several interesting questions. When and how do different effectors bind FAK? And what contributions do individual SH2- and SH3-containing binding partners make to the signaling pathways downstream of activated FAK? One interesting possibility is that the spatial and temporal activation of FAK in different cellular compartments (e.g. phosphorylation of Tyr397 or other sites in adhesion complexes, focal adhesions or growth factor complexes) provides a `switch' allowing FAK to signal to multiple different downstream pathways, depending on the structural context of FAK activation. Such selective activation of FAK could result in different physiological outcomes.
![]() |
The role of FAK in cell adhesion and migration |
---|
Turnover of adhesions also requires the functional interactions between
several FAK-interacting proteins (Webb et
al., 2002). For example, cells lacking paxillin expression, Cas
expression or Src family kinase expression all exhibit defects in adhesion
turnover (Klinghoffer et al.,
1999
), (Webb and Horwitz, personal communication). These
observations argue that FAK is a critical component of a pathway leading to
signals that either positively or negatively modulate the assembly and
breakdown of adhesions at the leading and/or trailing edges of migrating cells
(Webb et al., 2002
).
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Downstream signals multiple paths to small GTPases |
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Paxillin is proposed to play a role in targeting effectors of activated Rac
rather than stimulating Rac activation
(Brown et al., 2002;
Manser et al., 1997
). The
N-terminal region of paxillin contains five copies of a leucine-rich repeat
termed the LD motif, which comprise the binding sites for FAK and vinculin
(Turner, 2000b
). LD4 also
binds a complex of proteins containing PAK (p21-activated kinase), PIX
(PAK-interacting exchange factor) and a multidomain ARF-GAP protein, PKL
(paxillin-kinase linker) (Bagrodia et al.,
1999
; Bagrodia and Cerione,
1999
; Turner et al.,
1999
). As its name implies, PKL recruits PIX to adhesion
structures by binding to paxillin. Perturbation of this process by
overexpression of the paxillin LD4 domain significantly reduces migration of
cells into a wound (Turner et al.,
1999
). In contrast, expression of a paxillin variant lacking the
LD4 motif results in persistent Rac activation, increased membrane
protrusiveness, lamellipodia formation and a decrease in directional motility
(Brown et al., 2002
). Thus
appropriate localization of the paxillin-PKL-PIX complex appears important for
organization and turnover of adhesion complexes.
Members of the PIX/COOL family of proteins were originally identified as
regulators of PAK because of their ability to bind and activate it
(Manser et al., 1998;
Turner, 2000a
). Recent
evidence points to a role for the paxillin-PKL interaction in the recruitment
of activated PAK-PIX complexes to adhesions. Data support a model by which
Cdc42/Rac activation of PAK stimulates the binding of PAK to PIX, which in
turn induces binding of PAK-PIX to PKL-paxillin
(Brown et al., 2002
;
Turner, 2000a
). As a
consequence, activated PAK is targeted to newly formed (Rac-induced)
adhesions, which promotes PAK phosphorylation of proteins controlling adhesion
complex assembly and disassembly (e.g. MLC, MLCK and LIM kinase)
(Kumar and Vadlamudi,
2002
).
Adhesion-induced phosphorylation of paxillin on Tyr31 and Tyr118 stimulates
Crk binding to paxillin and formation of paxillin-Crk complexes
(Turner, 2000b). It is unclear
whether paxillin-Crk signals to the DOCK180-ELMO complex. However, tyrosine
phosphorylation of paxillin has been implicated in the binding of two other
protein tyrosine kinases: Csk, a negative regulator of Src family kinases, and
Abl. The role of these kinases in downstream signaling by paxillin is unclear
(Turner, 2000a
).
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Cooperative signals with growth factors |
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FAK and cancer |
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![]() |
Prospects for the next ten years |
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Acknowledgments |
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