13. Υποδοχείς κινάσες Ser-Thr

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    Ser/Thr

    1. TGFTGF

    TGF

    Smads

    TGFSmads

    2. TGFTGF-

    3. (Bone morphogenetic protein)

    13o

    TGF-

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    ,

    Ser/Thr.

    TGF- (transforming growth factor

    ). TGF,

    . TGF . TGF,

    . TGF -

    ( ),

    , .

    1. TGF-

    TGF-

    (transforming growth factor),

    . TGF-30 ,

    TGF-, (Bone Morphogenetic Protein:

    ) . TGF-

    TGF-1, TGF-2 TGF-3.

    .

    TGF-

    - (Ser/Thr).

    Ser/Thr.

    .

    TGF-R RI

    RI. ,

    .

    TGF-

    O TGF--,

    . 2--

    (pro-domain, LAT) 50-375 , COO-

    , TGF-.

    , , S-S, . TGF

    LSKL RKPK, -

    LAT , LTBP

    (Latent TGF-binding protein).

    .

    - LAT, LSKL,

    - -TGF. (13.1).

    TGF

    . TGF

    - -.

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    13.3RI RII.RI GS,

    GF.

    TGF-

    TGF-,

    . TGF -

    , ,

    TRTR.

    Ser/Thr, TR .

    : TGF

    RI, TRI.

    R

    TGF-TRII, -

    , TRII

    Ser/Thr

    TRI.

    RI

    (Gly/Ser), GS-

    box.

    13.2TGF-

    TGF-

    ,

    .[1]

    , ,

    S-S,. TGF

    LSKL RKPK, -LAT

    ,

    LTBP. [2]

    - -TGF

    ,

    .

    :Harvey Lodish, Molecular Cell Biology,2007.

    ,

    , S-S

    --

    TGF

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    RI .

    :

    TRII,

    , RI,

    .

    TGF

    ,

    Ser/Thr

    Tyr. trans-

    .

    Smads (Smad2, Smad3),

    RI

    (13.4).

    13.4

    TGF.

    O TGF-

    RI,

    RI,

    GS ,

    Smad 2/3,

    Smad4

    .AHarvey Lodish,

    Molecular Cell Biology, 2007.

    Smads

    Smads :

    1. R- Smads(receptor activated Smad) :

    TGF-(Smad2, Smad3)

    (Smad1, Smad5 Smad8)

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    2. Co-Smads (common mediator Smad) : Smad4

    R-Smads .

    3. I-Smads (inhibitory Smads): Smad,

    Smad6 Smad7.

    Smads TGF- Smad2 Smad3.RI

    Smads. Smad2,3 ,

    . Smad2,3

    Smad4 (Co-Smad). , Smad2/3-

    Smad4 , ,

    DNA, .

    Smads

    Smads

    , DNA . :

    MH1 N-Mad homology1

    Linker,

    2 C-Mad homology2

    1 2 ,

    .

    1 :

    1. : 1 2. Smad

    (TGF-).

    2. DNA: 1

    DNA . R-Smads

    Smad3 -hairpin,

    DNA, Smad2

    .

    3. .

    4. : Smads 1

    NLS (nuclear localization signal)

    Smads .

    (linker) 1 2,

    , :

    .

    , R-Smads 3 (Smurf1

    Smurf2) .

    NES -, Co-Smad

    .

    SAD (Smad activation domain), Co-Smad

    R-Smads.

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    2 : , (

    R-Smads), Smads .

    13.5Smad .

    1R-Smads, DNA,

    . 2

    TRI, Smad4

    DNA. R-Smads

    , 3 (Smurf1Smurf2) , Co-Smad NES SAD

    R-Smads .

    Lutz, P Knays, Integration of the TGF-pathway into the cellular signaling network, Cellular

    Signaling 14 (2002) 977-988.

    TGF-,

    .

    ;

    . : .

    , .

    TGF-.

    )

    (TGF-) .

    ,

    . ,

    RI

    Smad4

    DNA

    DNA

    DNA

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    .

    :

    - TGF-,

    (recyclingendosomes).

    - TGF-, (TRI/TRII)

    .

    (degrading lysosome).

    .

    13.6

    ) TGF-:

    (Recycling endosome).

    ) TGF-:

    (Degrading lysosome).

    Lutz, P Knays, Integration of the TGF-pathway into the cellular signalling network, Cellular

    Signalling 14 (2002) 977-988.

    )

    -

    TGF-.

    FKBP12 (FK binding protein 12kDa, 12 kDa

    FK). , FKBP12

    TRI , TRII . TGF-

    ) )

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    TRII FKBP12

    TRI .

    SARA (Smad anchor receptor activation)

    Smad2,3

    R . Smad2,3

    SARA Smad4.Dab2 (Disable-2)TGF-

    TRI TRII.

    , Smad

    .

    TRAP-1 (R-associated protein-1)

    TRII, TGF-

    TRA-1 . H TRAP-1

    Smad4,

    R-Smads Smad4.

    13.7 TGF.

    ,

    TGF-, TGF-.

    , ,

    . (TRIP-1, Dab-2, XIAP,

    STRAP, SNX6 Daxx)

    (), (SARA, Smad7,

    Smurf1/2) ()

    (TRAP-1, FKBP-12, SNX6). Lutz, P Knays, Integration of the TGF-pathway into the

    cellular signaling network, cellular signaling 14 (2002) 977-988.

    FKBP12

    Smurf1/2

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    TGF-

    Smad7, STRAP (serine/threonine kinase receptor-associated protein)

    Smad Smurf 1, Smurf 2 (Smad ubiquitination

    regulatory factors).

    Smad7Smad,

    Smad 1 2. o Smad7 R-Smads

    TGF-.

    Smad7, STRAP

    Smad7, -

    Smad7. Smurf1, Smurf2 E3

    Smad7 ,

    .

    13.8 Smurf1/2

    TGF.

    Smurf1/2

    Smad7

    TRI/II

    ,

    .

    Dijke P., Hill C., New

    insights into TGF--Smadsignaling, Trends in Biochem. Sci.,

    2004, 29, 265-273.

    TGF-,

    , TRIP-1 (TGF- receptor interacting

    protein). TRIP-1 PAI1 (plasminogen

    activator inhibitor-1 promoter),

    Smads TRI.

    TRIP-1

    .

    TAB1,

    SNX6 (Sorting nexin 6) DAXX.

    TAB 1 (TGF--activated kinase binding protein 1,

    ) 1 (TGF--activated kinase),

    p38 MARK JNK.

    1 Smad7,

    1, (x-linked inhibitor of apoptosis), 3

    - RI 1.

    TGF-, TGF-(13.7).

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    )

    TGF-: TGF-

    //Nodal (bone morphogenetic protein)/GDF

    (growth and differentiation factor)/MIS (Mullerian inhibiting substance).

    Ser/Thre,

    12 (7 RI 5 TRII). O RI ALK5(activin receptor-like kinase -5).

    .

    , , Smad

    .

    , III.

    I II,

    . III, ,

    . - ActRII (inhibin), - TGF.

    FSH .

    , ,

    TGFII.

    13.1. TGF

    Smads

    TGF1/3 TR-I (ALK-5) TR-II - Smad2/3

    TGF1/2/3 TR-I (ALK-5) TR-II TR-III (betaglycan) Smad2/3

    BMP2 BMPR-IA (ALK-3) BMPR-II - Smad1/5

    GDF5 ActR-I (L-3,6) ActR-IIB - Smad1/5

    ActR-II (ALK-4) ActR-IIB - Smad1/5

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    TGFSmads

    TGF

    Smads, .

    TGF:

    3-Akt. : GTP Rho

    JNK, 1 () p38, Ras

    ERK1/2.

    GTPRho ROCK,

    Limk2. Limk2 ,

    . ,

    TGF.

    2 p70S6K,

    .

    13.9TGF

    . GTPRho

    ROCK,

    Limk2. Limk2 ,

    .

    .

    Moustakas A., Heldin C., J. Cell Sci. 2005, 118,

    3573-3584.

    13.10TGF

    (G1 S)

    , Smad non-Smad.

    / Smad ,

    , .

    myc.

    / 2

    p70S6K,

    G1

    S. p70S5K

    G1. Moustakas A.,

    Heldin C., J. Cell Sci. 2005, 118, 3573-3584.

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    non-Smad ,

    .

    13.11TGF.

    Smad : O TGFR

    Smad2/3, , Smad4, ,

    DNA, SBE (Smad binding element)

    (TF, transcription factors), TBE

    (Transcrition factor Binding element).

    non-Smad : TGF

    (Rho/JNK/cJun, TAK/p38/ATF2, Ras/ERK/cJun), 3-

    2, p70S6K ().

    Wakefield L, Roberts A., TGF-signaling: positive and negative effects on tumorigenesis,

    Current Opinion in Genetics and Development, 2002, 12, 22-29.

    2. TGF-

    TGF-

    .

    ,

    TGF-

    . 74%

    85%

    TGF-. TGF-:

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    TGF-,

    Smads (Smad2,3,4), Smad6/7

    3 Smad, Smurf1/2).

    13.12

    TGF(, , TGF-) .

    //,

    /.

    .

    .Levy L., Hill C., Alterations in components of the TGF-superfamily signaling

    pathways in human cancer, Cytokine & Growth Factor Reviews 2006, 17, 41-58.

    TGF-

    RTK

    GTPRas, MAPK

    . Ras

    TGF-. Ras

    Smad4 . Smad4

    TGF

    Ras/ERK. , Ras Smads

    Smads ,

    TGIF (TG-interacting factor). GIF Smads

    TGF-.

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    TGF-, Smad7,

    Smad4, ,

    . Smad7 TGF-F.

    13.13TGF.

    Ras Smad4

    Smad (TGIF) . UV

    Smad7, Smad4.Wakefield L, Roberts A., TGF-signaling: positive and negative effects on tumorigenesis,

    Current Opinion in Genetics and Development, 2002, 12, 22-29.

    3. BMP (bone morphogenetic protein)

    , TGF-,

    .

    ,

    , , . knockouts

    . BMP TGF-

    R-Smads

    . BMP R-Smads

    Smad1, Smad5, Smad8. TRI-Smad,

    TGF-,

    RI L-45 .

    TGF- BMP ,

    Smads

    BMP TGF-.

    Smad non-Smad :

    : /1/ p38 RK.

    Raf

    MEK

    ERK

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    13.14BMP.

    Smad : (PFC:

    preformed hetero-oligomeric complex) II. ,

    Smad1/5/8, ,

    Smad4, , DNA,

    -.

    non-Smad : non-Smad ,

    , .

    (BISC: BMP-induced signaling complexes).

    (1/TAK1/p38/, Ras/ERK).

    Nohe A., Keating E., Knaus P., Petersen N., Signal transduction of bone morphogenetic protein

    receptors, Cellular Signalling, 2004, 16, 291-299.

    Birkey Reffey S, Wurthner GU, Parks WT, Roberts AB, Duckett CS. X-linked inhibitor of

    apoptosis protein functions as a cofactor in transforming growth factor-beta signaling. J

    Biol Chem2001, 276, 26542-9

    Choy L, Derynk R. The type II transforming growth factor (TGF-) receptor-interacting

    protein TRIP-1 acts as a modulator of the TGF- response. J Biol Chem 1998, 273,

    31455-62

    DaCosta S., Roberts A., Lateral signaling enhances TGF-response complexity, Trends inCell Biol., 2004, 14, 107-111

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    Dijke P., Hill C., New insights into TGF--Smad signaling, Trends in Biochem. Sci.,2004,

    29, 265-273

    Krauss Gerhard, Biochemistry of signal Transduction and Regulation, Wiley-VCH Verlag

    2001

    Kulkarni AB, Huh C-G, Becker D, et al.: Transforming growth factor 1 null mutation in

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    Lalage M wakefield, Yu-an Yang and Oksana Dukhanina, Transforming growth factor-and

    breast cancer: Lessons learned from genetically altered mouse modelsBreast cancer Res

    2000, 2(2), 100-106

    Lalage M Wakefield and Anita B Roberts, TGF-signaling: Positive and negative effects on

    tumorigenesis.Current Opinion in Genetics and Development2002, 12, 22-29

    Levy L., Hill C., Alterations in components of the TGF-superfamily signaling pathways in

    human cancer, Cytokine & Growth Factor Reviews2006, 17, 41-58

    Moustakas A., Heldin C-H., Non-Smad TGF-signals,J. Cell Science 2005, 118, 3573-3584

    Nohe A., Keating E., Knaus P., Petersen N., Signal transduction of bone morphogenetic

    protein receptors, Cellular Signalling,2004, 16, 291-299Lutz, P Knaus, Integration of TGF-pathway into the cellular signalling network, Cellular

    Signaling2002, 14, 977-988

    Parks WT, Frank DB, Huff C, Renfrew Haft C, Martin J, Meng X, et al. Sorting nexin 6, a

    novel SNX, interacts with the transforming growth factor-beta family of receptor serine-

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    Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, et al. XIAP, a cellular

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