Transcript TEC-FAMILY KINASES: REGULATORS OF T-HELPER

TEC-FAMILY KINASES:
REGULATORS OF
T-HELPER-CELL DIFFERENTIATION
Pamela L.Schwartzberg, Lisa D.Finkelstein and Julie A.Readeinger
Nature Reviews Immunology.
2005 Apr;5(4):284-95. Review.
Laboratory of Biochemistry
KIM .Yong-Joong
2006.11.15
Abstract
• The TEC family now consists of five members.
– TEC (tyrosine kinase expressed in hepatocellular carcinoma)
– BTK (Bruton’s tyrosine kinase)
– ITK (interleukin-2 (IL-2)-inducible T-cell kinase; also known as EMT
or TSK)
– RLK (resting lymphocyte kinase; also known as TXK)
– BMX (bone-marrow tyrosine kinase gene on chromosome X; also
known as ETK)
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TEC-family kinases
• The TEC-family kinases, they have an amino-terminal
PtdIns(3,4,5)P3 binding PH domain, which is followed by a
TEC-homology domain that contains one or two proline-rich
regions (PRRs), then SRC homology 3 (SH3) and SH2 proteininteraction domains, and a carboxyterminal kinase domain.
• The atypical TEC kinase has a palmitoylated string of
cysteine residues, which leads to constitutive membrane
association of RLK,independent of PI3K activity.
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Figure 1| Structure and activation of TEC-family kinases.
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Figure 2 | TEC-family kinases in T-cell-receptor- signaling
pathways.
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Figure 3 | T-cell receptors and chemokine receptors
signal through TEC-family kinases.
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TEC-family kinases
• several interrelated steps are required to Activation of
TEC-family kinases :
– first, recruitment to the plasma membrane through interactions
between their pleckstrin homology domains and the products of PI3K
and/or other proteins.
– second, phosphorylation by SRC-family kinases.
– third, interactions with other proteins that bring the TEC-family
kinases into antigen-receptor signaling complexes.
– In addition, TEC-family kinases are thought to be regulated by
conformational changes directed by intra- and intermolecular
interactions involving their SH2 domains, SH3 domains and PRRs.
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Roles for TEC kinases in T cells
• Phospholipase C-γ activation and gene transcription.
– TEC kinases are activated through phosphorylation by SRC-family
kinases, such as LCK, and recruitment to the plasma membrane
through binding of PtdIns(3,4,5)P3, where they are brought into TCR
signaling complexes through interactions with SLP76, LAT and other
molecules.
– Consistent with the expression patterns of TEC kinases, mice
deficient in ITK show moderately severe defects in T-cell function,
whereas relatively minor defects are observed in RLK- deficient
mice; so far, there are no reported T-cell defects in TEC-deficient
mice.
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Roles for TEC kinases in T cells
• Actin reorganization.
– When T cells are stimulated by APCs, they become rapidly polarized
with recruitment of F-actin and signaling molecules to the site of
TCR stimulation, where these molecules are organized into a
structure known as the immunological synapse.
– ITK-deficient T cells have reduced F-actin polarization after TCR
stimulation.
• Chemokine-mediated signaling.
– TEC kinases influence actin reorganization and cell polarization
downstream of both the TCR and chemokine receptors (Fig. 1).
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Roles for TEC kinases in T cells
• Consequences for T-cell function.
– Although ITK and RLK are important intermediates in T-cell signaling,
it should also be noted that mutations of these TEC kinases do not
completely block either TCR- or chemokine-receptor-mediated
responses.
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RLK and ITK in TH-cell differentiation
• After stimulation with antigen, naive CD4+ TH cells
differentiate into two distinct subsets — TH1 and TH2 cells
— which are responsible for cell-mediated and humoral immune
responses, respectively65 (FIG. 4A).
• These subsets are defined mainly by their unique cytokine
profiles.TH1 cells express interferon-γ (IFN-γ), IL-2 and
lymphotoxin, whereas TH2 cells produce IL-4, IL-5, IL-9, IL10 and IL-13.
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Interpreting the role of TEC kinases in TH cells
• RLK (resting lymphocyte
kinase) and ITK
(interleukin-2 (IL-2)inducible T-cell kinase)
have been implicated in
differentiation into TH1 and
TH2 cells, respectively.
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Interpreting the role of TEC kinases in TH cells
• Differential expression of
ITK and RLK.
– RLK overexpression increases
interferon-γ (IFN-γ)
production and shifts T cells
towards TH1-cell
development.
– ITK deficiency results in
defective NFATc1(nuclear
factor of activated T cells,
cytoplasmic, calcineurindependent 1) activation,
increased T-bet expression
and an inability to mount an
effective TH2-cell response.
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Interpreting the role of TEC kinases in TH cells
• Deficiency in both RLK and
ITK leads not only to
defective NFATc1 activation
but also to increased GATA3
levels.
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Fig 4.A
Fig 4.B
Fig 4.C
Fig 4.D
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Potential roles for TEC in T cells
• TEC seems to have distinct localization and signaling
attributes compared with other TEC kinases.
• Overexpression of TEC induces activation of NFAT and AP1
reporter genes and inositol phosphatases, SHIP1 and SHIP2.
• Although these data indicate that TEC might have a unique
role in T cells, it remains to be determined whether TEC is
involved in TH-Cell development.
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Concluding remarks
• Given the complex nature of TH-cell differentiation, the
question remains whether TEC kinases are good therapeutic
targets for diseases that are associated with imbalances in
TH-cell subsets. For RLK, the answer is unclear.
• Further analyses of the potential effects of RLK inhibition
are required.
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