Laboratory of Biochemistry KIM .Yong-Joong 2006.11.15

TEC-FAMILY KINASES:TEC-FAMILY KINASES:REGULATORS OFREGULATORS OFT-HELPER-CELL DIFFERENTIATIONT-HELPER-CELL DIFFERENTIATION Pamela L.Schwartzberg, Lisa D.Finkelstein and Julie A.ReadeingerPamela L.Schwartzberg, Lisa D.Finkelstein and Julie A.Readeinger Nature Reviews Immunology.Nature Reviews Immunology.2005 Apr;5(4):284-95. Review.2005 Apr;5(4):284-95. Review.

Laboratory of BiochemistryLaboratory of BiochemistryKIM .Yong-JoongKIM .Yong-Joong

2006.11.152006.11.15

LAB of BiochemistryLAB of Biochemistry 22

Abstract• The TEC family now consists of five members.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)


TEC-family kinases

• The TEC-family kinases, they have an amino-terminal PtdIns(3,The TEC-family kinases, they have an amino-terminal PtdIns(3,4,5)P3 binding PH domain, which is followed by a TEC-homolog4,5)P3 binding PH domain, which is followed by a TEC-homology domain that contains one or two proline-rich regions (PRRy domain that contains one or two proline-rich regions (PRRs), then SRC homology 3 (SH3) and SH2 protein-interaction ds), then SRC homology 3 (SH3) and SH2 protein-interaction domains, and a carboxyterminal kinase domain.omains, and a carboxyterminal kinase domain.

• The atypical TEC kinase has a palmitoylated string of cysteiThe atypical TEC kinase has a palmitoylated string of cysteine residues, which leads to constitutive membrane associatione residues, which leads to constitutive membrane association of RLK,independent of PI3K activity.n of RLK,independent of PI3K activity.


Figure 1| Structure and activation of TEC-family kinases.


Figure 2 | TEC-family kinases in T-cell-receptor- signaling pathways.


Figure 3 | T-cell receptors and chemokine receptors signal through TEC-family kinases.


TEC-family kinases• several interrelated steps are required to Activation of TECseveral interrelated steps are required to Activation of TEC

-family kinases :-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 in

to antigen-receptor signaling complexes.– In addition, TEC-family kinases are thought to be regulated by conformati

onal changes directed by intra- and intermolecular interactions involving their SH2 domains, SH3 domains and PRRs.


Roles for TEC kinases in T cells• Phospholipase C-γ activation and gene transcription.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.


Roles for TEC kinases in T cells• Actin reorganization.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.Chemokine-mediated signaling.– TEC kinases influence actin reorganization and cell polarization downstre

am of both the TCR and chemokine receptors (Fig. 1).


Roles for TEC kinases in T cells• Consequences for T-cell function.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.


RLK and ITK in TH-cell differentiation• After stimulation with antigen, naive CD4+ TH cells differenAfter stimulation with antigen, naive CD4+ TH cells differen

tiate into two distinct subsets — TH1 and TH2 cells — which tiate into two distinct subsets — TH1 and TH2 cells — which are responsible for cell-mediated and humoral immune responsare responsible for cell-mediated and humoral immune responses, respectively65 (FIG. 4A).es, respectively65 (FIG. 4A).

• These subsets are defined mainly by their unique cytokine prThese subsets are defined mainly by their unique cytokine profiles.TH1 cells express interferon-γ (IFN-γ), IL-2 and lympofiles.TH1 cells express interferon-γ (IFN-γ), IL-2 and lymphotoxin, whereas TH2 cells produce IL-4, IL-5, IL-9, IL-10 ahotoxin, whereas TH2 cells produce IL-4, IL-5, IL-9, IL-10 and IL-13.nd IL-13.


Interpreting the role of TEC kinases in TH cells

• RLK (resting lymphocyte kinaRLK (resting lymphocyte kinase) and ITK (interleukin-2 se) and ITK (interleukin-2 (IL-2)-inducible T-cell kina(IL-2)-inducible T-cell kinase) have been implicated in se) have been implicated in differentiation into TH1 and differentiation into TH1 and TH2 cells, respectively.TH2 cells, respectively.


Interpreting the role of TEC kinases in TH cells• Differential expression of IDifferential expression of I

TK and RLK.TK and RLK.– RLK overexpression increases i

nterferon-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, calcineurin-dependent 1) activation, increased T-bet expression and an inability to mount an effective TH2-cell response.


Interpreting the role of TEC kinases in TH cells

• Deficiency in both RLK Deficiency in both RLK and ITK leads not only and ITK leads not only to defective NFATc1 to defective NFATc1 activation but also to activation but also to increased GATA3 levels.increased GATA3 levels.


Fig 4.AFig 4.A

Fig 4.BFig 4.B

Fig 4.CFig 4.C

Fig 4.DFig 4.D


Potential roles for TEC in T cells• TEC seems to have distinct localization and signaling attribTEC seems to have distinct localization and signaling attrib

utes compared with other TEC kinases.utes compared with other TEC kinases.

• Overexpression of TEC induces activation of NFAT and AP1 repOverexpression of TEC induces activation of NFAT and AP1 reporter genes and inositol phosphatases, SHIP1 and SHIP2.orter genes and inositol phosphatases, SHIP1 and SHIP2.

• Although these data indicate that TEC might have a unique roAlthough these data indicate that TEC might have a unique role in T cells, it remains to be determined whether TEC is inle in T cells, it remains to be determined whether TEC is involved in TH-Cell development.volved in TH-Cell development.


Concluding remarks• Given the complex nature of TH-cell Given the complex nature of TH-cell

differentiation, the question remains whether TEC differentiation, the question remains whether TEC kinases are good therapeutic targets for diseases kinases are good therapeutic targets for diseases that are associated with imbalances in TH-cell that are associated with imbalances in TH-cell subsets. For RLK, the answer is unclear.subsets. For RLK, the answer is unclear.

• Further analyses of the potential effects of RLK Further analyses of the potential effects of RLK inhibition are required.inhibition are required.

Laboratory of Biochemistry KIM .Yong-Joong 2006.11.15

Documents

Transcript of Laboratory of Biochemistry KIM .Yong-Joong 2006.11.15