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Ser/Thr
1. TGFTGF
TGF
Smads
TGFSmads
2. TGFTGF-
3. (Bone morphogenetic protein)
13o
TGF-
5/28/2018 13. Ser-Thr
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416
,
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
- -.
5/28/2018 13. Ser-Thr
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417
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
5/28/2018 13. Ser-Thr
4/16
418
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)
5/28/2018 13. Ser-Thr
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419
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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420
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
5/28/2018 13. Ser-Thr
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421
.
:
- 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-
) )
5/28/2018 13. Ser-Thr
8/16
422
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
5/28/2018 13. Ser-Thr
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423
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).
5/28/2018 13. Ser-Thr
10/16
424
)
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
5/28/2018 13. Ser-Thr
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425
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.
5/28/2018 13. Ser-Thr
12/16
426
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-:
5/28/2018 13. Ser-Thr
13/16
427
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-.
5/28/2018 13. Ser-Thr
14/16
428
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
5/28/2018 13. Ser-Thr
15/16
429
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
5/28/2018 13. Ser-Thr
16/16
430
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
mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA1993, 90, 77-774
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-
threonine kinases. J Biol Chem2001, 276, 19332-9
Perlman R, Shiemann WP, Brooks MW, Lodish HF, Weinberg RA. TGF-beta-induced
apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell
Biol 2001; 3: 708-14.
Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, et al. XIAP, a cellular
member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in
the BMP signaling pathway,EMBO J1999, 18, 179-87
Yang X, Khosravi-Far R, Chang HY, Baltimore D. Daxx, a novel Fas-binding protein that
activates JNK and apoptosis. Cell1997, 89, 1067-76