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.

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TEC-FAMILY KINASESREGULATORS OFT-HELPER-CELL
DIFFERENTIATION Pamela L.Schwartzberg, Lisa
D.Finkelstein and Julie A.Readeinger Nature
Reviews Immunology.2005 Apr5(4)284-95. Review.

• Laboratory of Biochemistry
• KIM .Yong-Joong
• 2006.11.15

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Abstract

• The TEC family now consists of five members.
• TEC (tyrosine kinase expressed in hepatocellular
  carcinoma)
• BTK (Brutons 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
  protein-interaction 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-? 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-?
  (IFN-?), IL-2 and lymphotoxin, whereas TH2 cells
  produce IL-4, IL-5, IL-9, IL-10 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-? (IFN-?)
  production and shifts T cells towards TH1-cell
  development.
• ITK deficiency results in defective
  NFATc1(nuclear factor of activated T cells,
  cytoplasmic, calcineurin-dependent 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.