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  • 1.

    2. Jak-STAT Janus STAT

    3. - - - -

    4. -

    12o

    Stat-3

  • 388

    :

    1. , (RTK: receptors tyrosine kinases). .

    2. . , (associated tyrosine kinase), . . , , , . .

    , - - .

    1.

    (

  • 389

    . , , . , .

    , .

    12.2

    . .

    . , IL-4, IL-5, IL-6 IL-10, - -.

    - -, . - -, . . , - -.

    , ( MHC II -) - - -2 (IL-2). IL-2 , . , , -, -, -. - , -. , , .

  • 390

    12.2 . C- -. -. , L-2. -, .

    F (tumor necrosis factor) -, -.

    (Kd 10-10-10-12 M). picomoles.

    , , :

    1. IL-1, .

    2. ( ), IL2-9, IL11-13, GM-CSF (granulocyte-macrophage colony stimulating factor), G-CSF (granulocyte colony stimulating factor), LIF (leukemia inhibitory factor), CNTF (ciliary neurotrophic factor), OSM (oncostatine), . 4 , WSXWS (W: , S: , : ).

    3. ( ) , , IL-10. 4 , WSXWS.

    4. TNF , CD40 Fas.

    -

  • 391

    , , GPCRs.

    12.3 ,

    . () IL-1 . . () ( ). () ( ). () TNF , CD40 Fas.

    2 3 . - C- .

    - . , - IL-2 IL-4, IL-7 IL-9. gp130 -.

    , , . IL-6 - gp130 . : , - - - .

  • 392

    12.4 -, Epo-R G-

    CSFR, - IL-6, IL-2, IL-4 LIF (leukemia inhibitory factor). , gp130, -.

    , , . :

    1. . , .

    2. , - , .

    , , . Src Jak.

    Lck (p56lck) Src, IL-2. -2 (IL-2) , , . 2 , . Lck IL-2 . - Lck , .

    Lck, IL-2, Fyn Jak1 Jak3 (Janus kinases).

  • 393

    , .

    Jak1Jak2

    Lck

    PI3-K

    c-myc c-fosPLC

    12.5 2. IL2 Jak1 Jak3. - Stat5. , Shc, SH2 , Ras. Stat5 . IL-2 Lck Syk, c-Myc c-Fos.

    , . SH2 , . 3- Shc , Ras . Ras Shc/Grb2/mSos.

    .

    Jak-Stat Ras MAP C 3-

  • 394

    2. Jak-Stat

    Jak-Stat . .

    Janus

    Janus (Jaks). Janus () , Jak , , . , JAK Just another kinase. Jak (Jak1, Jak2, Jak3, Jak4). Jak . , . C

    12.6 Jak . JH1 (JH: Janus kinase homology region)

    . JH2 . - Jak.

    Jak

    , , Box1 Box2. , Jak . Jak - .

    12.7 Jak

    . , Jak trans-. Jak . .

    C D E JH1 JH2

  • 395

    ( ) Jak . Jak 6 (Jak1 Jak2), (Jak1 Tyk1). , Jak STAT, .

    12.8 IL-6, Jak1 Jak2, INF, Jak1 Tyk. , Jak STAT, , ISRE (interferon stimulated response element) - .

    STAT

    STAT , . 7 STAT : STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b STAT6. . , , , , , , . . STATs , 50 STATs .

    IL-6

    IFN

    IL-6 IFN

  • 396

    STAT : STAT STATs : ,

    , N (-domain), coiled coil , STAT DNA (DNA domain), (LD: linker domain) - SH2 . STATs ().

    STATs (S) TAD (transcriptional activation domain) COOH .

    NH2- -COOH

    TAD

    12.9 STATs (). T STAT (). (a) - STAT4. (- -). (b) STAT1

    GAS DNA. coiled-coil , DNA binding domains, SH2 .

    STATs

    STAT -1. 1 (IFN IFN) - , STATs. o IFNa, IFN-stimulated gene response element (ISRE), ISGF3 (IFN-stimulated gene factor 3). o IFN-stimulated gene response element (GAS) , , GAF (gamma-activated factor). , ISGF3 GAF STATs. ISGF3 STAT1, STAT2 p48/ISGF3/IRF9 ( STAT, IFN-regulatory factors) GAF STAT1.

    7 STAT : STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b STAT6. , .

    ND Coiled-coil DNA LD SH2 Y S

    P P

  • 397

    STATs STATs , SH2 ,

    JAK. . STATs . STATs , DNA ( interferon stimulated response element gamma activation site), . STAT2, STATs .

    12.10 STATs, JAK . orvath C.M., Stat proteins and transcriptional responses to extracellular signals, Trends in Biochem. Sci., 2000, 25, 496-502

    STATs STTs GTP Ran (importin), , . STAT NLS (nuclear localization sequence), . GTP Ran, , . , Ran GTP.

    STAT DNA

    - - STAT GAS (gamma activation sites) DNA, --. GAS (gene promoters), PIE: prolactin-inducible element .

    - STAT1-STA2 p48/ISGF3, ISRE DNA. STAT - GAS.

    STATs

    STAT

  • 398

    STATs DNA, enhancer binding protein ( SP-1, GR), STAT .

    DNA STATs TAD, -, .

    12.11 STATs, DNA. () STAT

    GAS (gamma activation sites) DNA, --. () - STAT1-STA2 p48/ISGF3, ISRE DNA. () STAT - GAS. () STATs DNA, enhancer binding protein ( SP-1, GR), STAT . () DNA STATs TAD, -, .

    orvath C.M., Stat proteins and transcriptional responses to extracellular signals, Trends in Biochem. Sci., 2000, 25, 496-502

    () - ()

    ()

    /

    () DNA

    () GAS element

    / RNA

  • 399

    STAT STAT :

    1. NES 2. , STAT

    DNA . DNA, STAT1 NES, , Ran.

    STATs

    Stat1 Stat. Stat1 , , IFNs. Stat2 Stat GAS DNA. Stat2 , , . IFN/ Stat1. Stat3 , , . knock-out . Stat3 , . Stat4 IL-12. Stat4 . Stat4 B IgE. Stat5, 5 5 . Stat5 . Stat5 IL-3, IL-12 GM-CSF. . Stat5 , T . Stat6 .

    IL-4 . - B . Stat6 C/EBP IgE.

    3. - -

    - - , . , .

  • 400

    - , , - - . - ,

    - , - - . - ( ) . MHC (major histocompatibility complex) - - ( 12.2). MHC . - - . , . - -,

    - , -.

    - - , , .

    CD3

    12.12 -. Ti, CD3. ITAM. R. Goldsby, T. Kindt and J. Kuby, Immunology, Freeman editions, 5th edition, 2003.

    Ti , . ,

    i CD3

  • 401

    CD3, , , , . Tyr Leu (D/E)XXYXXL(X)6-8YXXL (ARAM: antigen recognition activation motif) (ITAM: immunoreceptor tyrosine-based activation motif). ARAM CD3, CD3, CD3 . ARAM -. -, Tyr ITAMs (ARAMs) , SH2 . .

    - -. -. CD4 CD8, - - , . - , Src. , .

    TCR (T cell Receptor) MHC- 7 ( -) CD28 ( -).

    12.13 - TCR (T cell receptor).

    - (THelper) - TCR CD4, - (Tcytotoxic), - CD8. - MHC-II (o CD4) MHC- (o CD8) TCR- -MHC. - -, CD28-B7, CD45R-CD22, CD2-LFA-3. R. Goldsby, T. Kindt and J. Kuby, Immunology, Freeman editions, 5th edition, 2003.

  • 402

    12.14 () - CD4 CD8. () CD4

    CII- (pMHCII) TCR.

    - -

    - -