National Human Genome Research Institute, 49 Convent Drive, 49/4A38, National Institutes of Health, Bethesda, MD 20892, USA
* Author for correspondence (e-mail: pams{at}nhgri.nih.gov )
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Summary |
---|
Key words: Tyrosine kinase, Pleckstrin homology domain, Phospholipase C-, Calcium mobilization, Actin cytoskeleton
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Introduction |
---|
|
Cells lacking Btk, including cells from XLA patients and mutants of the
chicken DT-40 B cell lymphoma line, exhibit defective signaling from the B
cell receptor with abnormal activation of PLC- and decreased
Ca2+ mobilization (Fluckiger et
al., 1998
; Takata and
Kurosaki, 1996
). Similar results are found in mast and T cells
lacking Tec kinases (Kawakami et al.,
1999
; Liu et al.,
1998
; Schaeffer et al.,
1999
). In the past few years, a large body of work has helped
examine how Tec kinases participate in the activation of PLC-
in
antigen receptor signaling (Lewis et al.,
2001
). However, Tec family kinases have also been implicated in
multiple signaling pathways from a wide range of cell surface receptors
(Qiu and Kung, 2000
). Here, we
will review how the Tec kinases are activated, their roles in downstream
signaling pathways and the consequences of their mutations for cellular
physiology with an emphasis on T lymphocyte antigen receptor signaling.
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Structure and expression of Tec kinases |
---|
Tec kinases possess modular organizations similar to Src family kinases
(SFKs), having unique N-termini followed by Src homology 3 (SH3) and Src
homology 2 (SH2) protein interaction domains and a tyrosine kinase catalytic
domain (SH1) (Fig. 1)
(Smith et al., 2001). However,
unlike Src kinases, Tec kinases lack N-terminal myristoylation sites and
regulatory C-terminal tyrosine residues. Instead, Tec kinases are
distinguished by an N-terminal PH domain and adjacent Tec homology (TH)
region, which includes a Btk homology (BH) region and one or two proline-rich
regions (PR) (except Rlk/Txk, Bmx/Etk and Dsrc29; see
Fig. 1a). These unique features
contribute to the regulation of these kinases through protein-protein and
protein-lipid interaction and may help determine their varied functions in
different signaling pathways. Numerous signaling molecules can interact with
each of these domains (Fig. 1b)
(Qiu and Kung, 2000
).
PH domain
The PH domain is a conserved region that can bind both to proteins,
including heterotrimeric G-protein subunits, isoforms of protein kinase C
(PKC), transcription factors, F-actin, Vav, Fas, and focal adhesion kinase
(FAK), and to phospholipids (Fig.
1b) (Qiu and Kung,
2000). Biochemical analyses demonstrate that the PH domain of Btk
preferentially binds to PtdIns(3,4,5)P3 and
Ins(1,3,4,5)P4 (Kojima
et al., 1997
; Rameh et al.,
1997
; Salim et al.,
1996
). Interactions between the PH domain and phopholipids are
critical for regulating membrane targeting of most Tec kinases in response to
extracellular stimuli (Fig. 2
and below). Recently, PtdIns(3,4,5)P3 binding of the PH
domain was found to increase Btk kinase activity in vitro
(Saito et al., 2001
).
Moreover, the combined PH-TH region of Btk also influences protein substrate
recognition and binding, suggesting that these domains may play multiple roles
in Tec kinase function (Lowry et al.,
2001
). Two recently identified inhibitors of Btk kinase activity,
Ibtk and Bam11, interact with the PH domain of Btk
(Kikuchi et al., 2000
;
Liu et al., 2001
).
|
TH (BH and PR) domain
The Btk homology (BH) domain is characterized by a zinc-binding sequence
with homology to Ras-GAP (Smith et al.,
2001). Tec kinases also possess one or two proline-rich sequences
(PR), which were first shown to be binding partners for the SH3 domains of the
Src kinases Fyn, Hck and Lyn (Cheng et
al., 1994
). However, a second important regulatory function for
the PR region has been suggested from NMR studies demonstrating an
intramolecular interaction between the PR and SH3 domains of Itk
(Andreotti et al., 1997
). More
recent data suggest that the PR-SH3 interactions can occur in several Tec
family kinases, but in some cases there may be a balance between
intramolecular and intermolecular interactions
(Brazin et al., 2000
;
Hansson et al., 2001
;
Laederach et al., 2002
;
Pursglove et al., 2002
).
Disruption of these interactions through binding to other molecules may
activate Itk and Btk. A conserved serine at the BH-PR boundary is a potential
PKC-phosphorylation site, which can alter membrane association and activity of
Btk (Kang et al., 2001
).
SH3 domain
The SH3 domain was first described as a conserved region of SFK that
interacts with proline-rich regions
(Pawson and Gish, 1992). In
Tec kinases, these domains are important for intramolecular interactions as
well as interactions with other signaling molecules. Mutations of the SH3
domain lead to increased transforming activity of an activated allele of Btk,
which is consistent with an inhibitory interaction with the PR domain
(Afar et al., 1996
;
Park et al., 1996
). For Btk,
autophosphorylation of a tyrosine residue (Y233) in the SH3 domain
(Park et al., 1996
) can change
the affinity of the SH3 domain for certain binding partners and may relieve
the interaction between the PR and SH3 domains
(Morrogh et al., 1999
).
SH2 domain
The SH2 domain is a protein interaction domain conserved among many
signaling molecules that bind to phosphorylated tyrosine residues in the
context of specific peptide sequences
(Pawson and Gish, 1992). For
the Tec kinases, the SH2 domain is required for interactions with antigen
receptor signaling intermediates, SLP76 and BLNK
(Bunnell et al., 2000
;
Hashimoto et al., 1999
;
Su et al., 1999
). Recent
evidence suggests that isomerization of a proline in the SH2 domain of Itk by
the prolyl-isomerase cyclophilin contributes to regulation of Itk: inhibition
of cyclophilin by Cyclosporin A can increase Itk kinase activity
(Brazin et al., 2002
).
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Activation |
---|
This activation model has been supported by numerous observations. Mutation
of the Src family phosphorylation site or inhibition of Src kinases prevents
activation of Tec kinases (Chamorro et
al., 2001; Gibson et al.,
1996
; Heyeck et al.,
1997
; Rawlings et al.,
1996
). Mutation of the PH domain of Btk can cause both XLA in
human and xid in mice and prevents activation of Btk, Itk and Tec in
cell lines (August et al.,
1997
; Li et al.,
1997
; Satterthwaite and Witte,
2000
; Yang et al.,
2001
), indicating that the PH domain plays a crucial role in
regulation of Tec kinase function. Moreover, activation of Btk, Itk and Tec is
prevented by inhibitors of PI3K, and Btk kinase activity can be diminished by
SH2-containing inositol phosphatase SHIP1, which decreases the levels of
PtdIns(3,4,5)P3 (August
et al., 1997
; Li et al.,
1997
; Scharenberg and Kinet,
1998
). Likewise, B cells from mice with a targeted mutation of the
PI3K p85
subunit have phenotypes similar to those of xid and
Btk-/- mice (Fruman et al.,
1999
; Suzuki et al.,
1999
). Conversely, deficiency of the inositol phosphatase PTEN
leads to constitutive membrane association of Itk in the Jurkat T cells
(Shan et al., 2000
). Note that
PI3K p110
-/- mice have T cell proliferation defects similar
to Itk-/- mice, raising the possibility that this G-protein-coupled
PI3K may also contribute to activation of Tec kinases in T cells
(Sasaki et al., 2000
).
Recent evidence suggests that the interaction of the PH domain with
PtdIns(3,4,5)P3 targets Tec kinases to specific membrane
microdomains, referred to as Rafts or glycolipid-enriched membranes (GEMs),
where signaling molecules convene upon antigen receptor activation
(Simons and Ikonen, 1997). Itk
translocates to GEMs upon CD3-TCR stimulation in a
PtdIns(3,4,5)P3- and PH-domain-dependent manner
(Bunnell et al., 2000
;
Shan et al., 2000
;
Woods et al., 2001
). Similar
results have been found for Btk (Guo et
al., 2000
). Intriguingly, both Btk and Bmx physically interact
with caveolin-1, a primary protein component of caveolae, a
glycolipid-enriched membrane compartment
(Vargas et al., 2001
).
Although most Tec kinases are regulated in this fashion, the atypical Tec
kinase Rlk/Txk lacks a PH domain. Rlk is activated by SFKs; however, unlike
other Tec kinases, Rlk is activated independently of PI3K
(Debnath et al., 1999).
Instead, Rlk possesses a repeated cysteine motif
(Fig. 1a), which is
palmitoylated and can also target Rlk/Txk to GEMs
(Czar et al., 2001
).
Additionally, a shorter form of Rlk, generated by internal translational
initiation, lacks this cysteine motif and can localize to the nucleus
(Debnath et al., 1999
). Upon
TCR activation, a fraction of Rlk translocates to the nucleus, which suggests
that Rlk may have distinct cytosolic and nuclear functions
(Debnath et al., 1999
).
Although nuclear localization was thought to be a unique feature of Rlk,
evidence now suggests that both Btk and Itk can traffic to the nucleus upon
antigen receptor signaling (Perez-Villar
et al., 2001
; Webb et al.,
2000
).
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Other activation pathways |
---|
In addition to Btk and Itk, other Tec kinases also change localization in
response to extracellular stimuli. The PH domain of Etk binds to the FERM
domain of FAK upon extracellular matrix stimulation of integrins, which leads
to the activation of Etk (Chen et al.,
2001). Both Etk and Tec can associate with and be activated by a
number of receptor tyrosine kinases as well as cytokine receptors
(Mano, 1999
;
Rajantie et al., 2001
).
Activation of the tyrosine kinase receptor Kit by stem cell factor induces
formation of a Lyn-Tec-Dok-1 complex and activation of Tec, both of which are
prevented by PI3K inhibition (van Dijk et
al., 2000
). Stimulation of prolactin receptor (PRLr), a member of
the cytokine receptor superfamily, induces activation of Tec and association
of both Tec and Vav with the intracellular domain of PRLr
(Kline et al., 2001
).
Together, these observations support a model in which Tec kinases require
proper targeting for their activation, probably through the interaction of
their PH domains with PtdIns(3,4,5)P3 or other signaling
molecules.
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Functions of Tec kinases |
---|
In T cells, initiation of T cell antigen receptor (TCR) signaling rapidly
activates the Src kinase Lck, which phosphorylates a series of conserved dual
tyrosines, the immunotyrosine activation motifs (ITAMs), on the invariant
chains of the TCR complex, which in turn recruit the Syk family kinase Zap70
through its dual SH2 domains (Fig.
3). Zap70 is then phosphorylated and activated by Lck
(Lin and Weiss, 2001;
Samelson, 2002
). Activated
Zap70 in turn phosphorylates a number of adaptor molecules, including a novel
transmembrane palmitoylated adaptor protein, LAT, which serves as a platform
for the recruitment of other signaling molecules. These include GRB-2, which
activates the Ras-Raf MAPK pathway, a related molecule, GADs, which binds to
the adaptor molecule SH2-domain-containing leukocyte protein of 76 kDa (SLP76)
via a proline domain-SH3 interaction, and PLC-
. SLP76 also serves as a
central component of this signaling complex: mutations of either LAT or SLP76
impair TCR activation of ERK and PLC-
in the Jurkat T cell-line and
prevent thymocyte maturation at early stages
(Clements et al., 1999
). Upon
TCR activation, SLP76 is phosphorylated by Zap70 and can bind to the guanine
nucleotide exchange factor Vav, the adaptor molecule Nck and the SH2 domain of
the Tec family kinase Itk (Bunnell et al.,
2000
; Clements et al.,
1999
). Secondary interactions with LAT through the Itk SH3 and SH2
domains and an interaction with PLC-
also contribute to interactions of
the Tec kinases in this complex (Bunnell
et al., 2000
; Perez-Villar and
Kanner, 1999
). In B cells, a similar signaling complex is
nucleated by the adaptor BLNK/SLP65, which recruits GRB2, PLC-
, Vav and
Btk (Kurosaki and Tsukada,
2000
). Reconstitution experiments have demonstrated that Btk
function requires both the PH domain and a functional SH2 domain, which bring
Btk into this signaling complex (Takata
and Kurosaki, 1996
).
|
Within this complex, the Tec kinases appear to be important for full
phosphorylation and activation of PLC-, an enzyme that cleaves
PtdIns(4,5)P2 to generate Ins(1,4,5)P3
and diacylglycerol (DAG) (Lewis et al.,
2001
; Rhee, 2001
;
Scharenberg and Kinet, 1998
).
Ins(1,4,5)P3 then binds to receptors on intracellular
organelles to release intracellular Ca2+, which leads to an influx
of Ca2+ from extracellular sources via store-operated (CRAC)
channels (Lewis, 2001
). B
cells from XLA patients, a mutant DT-40 chicken cell line that lacks Btk, and
T cells lacking Itk or Itk and Rlk, all show varying defects in PLC-
phosphorylation associated with decreased Ins(1,4,5)P3
production and Ca2+ mobilization
(Fluckiger et al., 1998
;
Liu et al., 1998
;
Schaeffer et al., 1999
;
Takata and Kurosaki, 1996
). In
particular, the late phase of Ca2+ influx from extracellular stores
is most affected in these cells. Although overexpression of Btk and Rlk can
increase tyrosine phosphorylation of PLC-
, whether phosphorylation is
the only contribution of Tec kinases to PLC-
activation and antigen
receptor signaling remains unclear
(Fluckiger et al., 1998
;
Veri et al., 2001
). Indeed,
one study of BTK-deficient DT40 cells showed that kinase-inactive BTK can also
improve Ca2+ mobilization in these cells
(Tomlinson et al., 2001
). This
observation, along with potential interactions of Tec kinases with PLC-
and SLP76, suggests additional functions for the Tec kinases
(Perez-Villar and Kanner,
1999
; Schneider et al.,
2000
).
Mutation of the Tec kinases is also associated with decreased activation of
MAP kinases. In T cells, activation of the MAP kinase ERK requires activation
of Ras-GRP (CD-GEFII), a novel Ras-GEF that contains a DAG-binding domain
(Ebinu et al., 2000).
Decreased activation of ERK has been observed in T cells lacking Itk or Rlk
and Itk and may be secondary to decreased production of DAG
(Schaeffer et al., 1999
). In
Btk-deficient B and mast cells, defective activation of the MAP kinases JNK
and p38 have also been reported, suggesting other connections to these kinases
(Jiang et al., 1998
;
Kawakami et al., 1997
). An
adaptor protein RIBP/LAD/TsAd, which can interact with both Rlk and Itk
(Rajagopal et al., 1999
), also
associates with MEKK-2, which activates the MEK-5/ERK5 pathway
(Sun et al., 2001
).
Note that, unlike mutations of the more proximal tyrosine kinases Lck and
Zap70, which eliminate Ca2+ mobilization and MAPK activation and
severely block thymocyte development, mutation of the Tec kinases in T cells
merely reduces the intensity and duration of these signals
(Schaeffer et al., 1999).
These observations have led to the concept that the Tec kinases have more
modulatory roles in antigen receptor signaling pathways. Whether this is
caused by redundancy of the Tec kinases or distinct functions for these
kinases is unclear. In B cells, regulation of Tec kinases may also contribute
to attenuation of B cell signaling through Fc
RIIb, which activates SHIP
(Scharenberg and Kinet, 1998
).
Finally, similar signaling complexes exist in mast cells and platelets
(Kawakami et al., 1999
),
although the organization and components vary slightly in each cell,
suggesting subtle differences in the requirements for activation and
downstream readouts influenced by Tec kinases
(Lewis et al., 2001
).
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Other downstream pathways |
---|
The first suggestion that Tec kinases may contribute to actin cytoskeletal
regulation came from studies of the Drosophila Tec family kinase
Tec29 (formerly Src29A), which is required for growth of ring canals
(actin-based intracellular bridges between nurse cells and the oocyte). A
similar phenotype is observed in mutants lacking the Drosophila Src
homolog Src64, which interacts with Tec29 and regulates its localization
(Guarnieri et al., 1998;
Roulier et al., 1998
).
In mammalian cells, interactions between the actin cytoskeleton and Tec
kinases have been suggested from several experiments. Using a GST-PH domain
fusion protein, F-actin was shown to associate directly with basic residues in
the N-terminal PH domain of Btk (Yao et
al., 1999). Stimulation through the insulin receptor or the
G-protein-coupled receptor CXCR4 leads to translocation of a BTK-GFP fusion
construct to membrane ruffles or lamellipodia, regions of the plasma membrane
formed by actin polymerization (Nore et
al., 2000
). In platelets, Btk localizes to the cytoskeleton upon
activation of the thrombin receptor
(Mukhopadhyay et al., 2001
).
This effect is regulated by the integrin
IIbß3 and depends on PI3K
activity. Furthermore, expression of kinase-inactive Itk reduces TCR-induced
actin polymerization in the Jurkat T cell-line
(Woods et al., 2001
). We have
also found that TCR-induced actin polymerization is impaired in Itk- and
Rlk/Itk-deficient T cells, supporting the functional importance of these
interactions (C. Labno, C. Lewis, J. Burkhardt and P.L.S., unpublished).
Further contributions of the Tec kinases to actin cytoskeleton regulation
have been suggested from interactions of Tec kinases with Vav and WASP, two
molecules involved in actin reorganization. Vav family members are GEFs that
facilitate the exchange of GDP for GTP to activate members of the Rho GTPase
family such as Rho, Rac and Cdc42, which are involved in actin cytoskeleton
reorganization (Bustelo,
2001). After stimulation with IL-3 and erythropoietin, Vav binds
to the Tec kinase via the TH domain of Tec
(Machide et al., 1995
). A
similar complex has been demonstrated with the Prolactin receptor
(Kline et al., 2001
). When
co-expressed in COS-1 cells, Tec was found to associate with Vav and enhance
Vav GEF activity. Although these data suggest that Tec kinases participate in
the activation of Vav, a recent report argues that Vav may also contribute to
the activation of Itk and Tec upon TCR activation
(Reynolds et al., 2002
),
suggesting more complex interactions between these two families of signaling
molecules.
WASP (Wiskott-Aldrich syndrome protein) is the gene product responsible for
the X-linked hereditary immunodeficiency Wiskott-Aldrich syndrome, a disease
associated with defective actin cytoskeleton regulation. Studies have shown
that activated CDC42 can bind to WASP, thereby enabling WASP to interact with
and activate the Arp2/3 complex, which nucleates new actin filaments
(Snapper and Rosen, 1999). A
search for Itk SH3 domain ligands revealed that Itk binds to a proline-rich
region of WASP (Bunnell et al.,
1996
). Further studies have demonstrated that Btk can physically
interact with WASP and that WASP can serve as a substrate for Btk
(Baba et al., 1999
;
Guinamard et al., 1998
).
Moreover, we have found defective activation of WASP downstream of the TCR in
Itk- and Rlk/Itk-deficient T cells (C. Labno, C. Lewis, P.L.S. and J.
Burkhardt, unpublished). The connection between the Tec kinases, WASP and Vav
is an intriguing area for future research.
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Roles in regulating cellular adhesion |
---|
Although it is not clear what pathways downstream of Tec kinases help
regulate increased cellular adhesion, there are several potential connections.
As noted above, Itk can regulate CD3/TCR-induced actin polymerization, which
influences downstream adhesion pathways. Another potential connection may
involve SLP76 and its binding partner - adhesion and
degranulation promoting adaptor protein
(ADAP; also known as SLAP-130 or Fyb) - a molecule that has recently been
shown to couple the TCR to integrin activation
(Griffiths et al., 2001;
Peterson et al., 2001
). Not
only do Tec kinases interact with SLP76, but Rlk can also tyrosine
phosphorylate SLP76 in T cells (Schneider
et al., 2000
). However, whether Tec kinases influence this pathway
of integrin regulation remains unclear.
Members of the PKC family of serine/threonine kinases also contribute to
integrin activation in lymphocytes, and several lines of evidence suggest that
Tec kinases are cross-regulated with PKC isoforms. Studies with the PH domain
of Btk reveal that it can interact with multiple PKCs, including PKCß and
PKC (Kang et al., 2001
;
Yao et al., 1994
), an isoform
that can physically associate with the actin cytoskeleton and is involved in
maintaining its integrity (Gomez et al.,
1995
). More recently, an interaction between Btk and PKC
was demonstrated in platelets, PKC
phosphorylating Btk on threonine and
Btk subsequently tyrosine phosphorylating PKC
to downregulate its
activity (Crosby and Poole,
2002
). PKC
has also been shown to be a component of the
T-cell-APC immunological synapse, a structure that relies heavily upon the
actin cytoskeleton (Monks et al.,
1998
). Therefore, regulation of PKC isoforms may provide a
connection between Tec family kinases, cytoskeletal reorganization and
integrin activation.
Finally, roles for the Tec kinases downstream of integrin receptors have
also been reported. In particular, upon engagement of integrins the FERM
domain of FAK can bind Etk/Bmx and activate its kinase
(Chen et al., 2001). Moreover,
kinase-inactive ETK blocks integrin-mediated migration. Thus, it is possible
that integrin function is regulated by Tec kinases at multiple steps.
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Transcriptional activation |
---|
Evidence also supports direct connections between Tec kinases and
transcription factors, however. In particular, interactions with and
phosphorylation of BAP 135/TFII-I, Bright, STAT3 and STAT5 have been reported
(Saharinen et al., 1997;
Tsai et al., 2000
;
Webb et al., 2000
;
Yang and Desiderio, 1997
).
Furthermore, it is also now clear that Rlk/Txk, Btk and Itk can all traffic to
the nucleus (Debnath et al.,
1999
; Perez-Villar et al.,
2001
; Webb et al.,
2000
). For Rlk/Txk and Btk, this localization may be linked to
transcriptional activation. Indeed, nuclear localization may be required for
Rlk to induce interferon-
(IFN-
) expression in the Jurkat T cell
line (Kashiwakura et al.,
1999
). A recent study extended these findings to show that Rlk
directly binds to DNA to stimulate expression of IFN-
, suggesting novel
roles for Tec kinases in the nucleus
(Takeba et al., 2002
).
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Other signaling pathways |
---|
|
In other cell types the Tec kinases have been implicated in additional
signaling pathways. The expression of Etk/Bmx in prostate and mammary
carcinoma lines suggested a role in cellular transformation. Further studies
have revealed that Etk is a critical intermediate in the STAT-3
phosphorylation and activation is required for v-Src transformation
(Tsai et al., 2000). Etk/Bmx
has also been implicated in G protein signaling pathways in endothelial cells,
where activation of Etk by G
subunits can lead to activation of serum
response factor transcriptional elements
(Mao et al., 1998
).
Intriguingly, this pathway appears to involve the small GTPase Rho, an
important modulator of the actin cytoskeleton. Etk has also been shown to
activate the p21 activated kinase, PAK, another molecule implicated in
cytoskeletal rearrangements
(Bagheri-Yarmand et al., 2001
).
Whether other Tec kinases activate similar signaling intermediates remains
unclear.
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Conclusions |
---|
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---|
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