Download - 12. Υποδοχείς που σχετίζονται με κινάσες Tyr
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2. Jak-STAT Janus STAT
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4. -
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Stat-3
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:
1. , (RTK: receptors tyrosine kinases). .
2. . , (associated tyrosine kinase), . . , , , . .
, - - .
1.
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. , , . , .
, .
12.2
. .
. , IL-4, IL-5, IL-6 IL-10, - -.
- -, . - -, . . , - -.
, ( MHC II -) - - -2 (IL-2). IL-2 , . , , -, -, -. - , -. , , .
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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.
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, , GPCRs.
12.3 ,
. () IL-1 . . () ( ). () ( ). () TNF , CD40 Fas.
2 3 . - C- .
- . , - IL-2 IL-4, IL-7 IL-9. gp130 -.
, , . IL-6 - gp130 . : , - - - .
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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).
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, .
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-
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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
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( ) 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
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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
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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
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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
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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. - -
- - , . , .
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- , , - - . - ,
- , - - . - ( ) . 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
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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.
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12.14 () - CD4 CD8. () CD4
CII- (pMHCII) TCR.
- -
- - . TCR Src ( Lck: Leucocyte specific kinase Fyn: Fgr/yes novel kinase) , . , Lck Fyn -, , CD4/8 -.
SH2 SH2 Kinase
Domain organization of ZAP-70
12.15 TCR
Lck, - CD4/8 Tyr -. The structure, regulation, and function of ZAP-70. Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, Weiss A. The structure, regulation, and function of ZAP-70. Immunol Rev. 2009, 228(1):41-57.
. .
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-70 ( associated protein 70: 70 kDa ), SH2 . , 70 Lck . ZAP-70 , -: L (Linker for activation of T-cells), .
LAT, Tyr, , SH2 , T-cell signalosome. Tyr132 LAT PLC, Tyr171 PI3-K , Tyr191 Grb2 , GDS (Grb-like adaptor downstream of Shc), Tyr226 Vav.
LAT adaptor protein
12.16 LAT ,
ZAP-70 (, , - ) . Houtman JC, Barda-Saad M, Samelson LE. Examining multiprotein signaling complexes from all angles, FEBS J. (2005) 272:5426-35.
SH3 ,
, T-cell signalosome. SH3 GADS SLP-76 (SH2-domain-containing leukocyte phosphoprotein of 76 kDa), Vav Itk (IL2-inducible T-cell kinase) TCR.
Itk : Itk , 3,4,5 PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 PtdIns(4,5)P2 3-, Lck. TCR, Itk PtdIns(3,4,5)P3 S2 LAT. , Lck
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SLP-76/Vav/Itk. Itk PLC- , .
12.17 TCR
Lck. Lck 3-, PtdIns(4,5)P2 PtdIns(3,4,5)P3. Itk PtdIns(3,4,5)P3 . Lck. Finkelstein LD, Schwartzberg PL. Tec kinases: shaping T-cell activation through actin, Trends Cell Biol. (2004) 14:443-51.
12.18 TCR. PLC PtdIns(4,5)P2 (2)
(IP3) (DAG). I3 - , Ca2+ . DAG Ca2+ PKC. , DAG RasGEF, RasGRP, PKC.
PC PKC, -, Ca2+ DAG.
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NFAT (nuclear factor for activated T-cells) JNK. PKC NFB. NFAT NFB IL-2. NF - .
Vav1 . Vav1, - ( Vav2, Vav3 ). DH , Rho GTP, (Ac) Tyr, , ( Vav GEF), SH3 SH2 . , -. TCR, Vav1 Tyr174 , SH2 o -cell signalosome ( SLP-76 LAT). , Vav1 GTP Rac Cdc42, WASP (Wiskott-Aldrish syndrome protein) Arp2/3 ( . 10, .328-329). WASP signalosome Nck (non-catalytic region of tyrosine kinase), SH2 SH3 . SH2 SLP76 SH3 WASP. WASP GTP Cdc42, .
Vav1
12.19 Vav1, -
. Vav Tyr (Ac) , GTP Cdc42 DH . Tybulewicz VL., Vav-family proteins in T-cell signaling, Curr Opin Immunol. (2005) 17(3):267-74.
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4.
. , . , , . . , (integrate) - - (Hynes, 1987).
. , , , . ( ) . - . . , , , .
12.18 , ,
().
: ,
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407
,
, ( ) 20-70 . 16 - 8 . , . , . . .
(clustering) , , ( ) ( ) . .
12.19 ()
. . Quin J, Vinogradova O and Plow E, Integrin bidirectional signaling: a molecular view, PLoS Biology, 2004, 2, 726-729.
: - : ,
( ) .
- : , . , . - - , .
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. , (focal adhesion sites). ( 50 ) , . . . , , , Ca2+- .
, - FAK, .
FAK (focal adhesion kinase)
, , (Tyr397). Y397 FAK SH2 , :
3- ( p85 ), -3- , . : Ser/Thr, ( ) ( Bad, -9..). , (, ) , .
Src, FAK Tyr (Tyr925), Shc, Grb2 Ras/RK, .
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12.20 () FAK (focal adhesion kinase),
1992 Src. () FAK, (FERM homology domain), FAT , , SH2 . Schwartz M.A., Integrin signalling revisited, Trends in Cell Biology, 2001, 11, 466-470. () FAK. FAK , , - . Schlaepfer D.D., Mitra S.K., Multiple connections link FAK to cell motility and invasion, Current Opinion in Genetics and Development, 2004, 14, 92-101.
. .
.
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12.21 (15) ()
FAK/PI3-K/PKB/BAD-Caspase9 () FAK/Src/Shc/Sos/Ras/MAPK . Gomperts et al, Signal Transduction, 2002, ELSEVIER.
12.22 FAK.
FAK . FAK Src, (Tyr925). Schlaepfer DD, Mitra SK, Ilic D. Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta. 2004, 1692(2-3), 77-102.
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FAK , / . , / .
Rho GTP. FAK p190RhoGEF, Rho. Rho ROCK, MLC (myosin light chain), MLCK ( ). GTP Rho: Tyr925 FAK Grb2, Ras/MEK/ERK Rho.
GTP Rho . Graf-GAP SH3 FAK Rho. , FAK/Src p190RhoGAP, Rho. . FAK , .
12.23 FAK
Rho. Schlaepfer D.D., Mitra S.K., Multiple connections link FAK to cell motility and invasion, Current Opinion in Genetics and Development, 2004, 14, 92-101.
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.
. FAK .
v-Src FAK . v-Src-FAK (invadopodia), (), . Tyr397 FAK Src . , FAK-Src JNK JNK, JSAP1, p130CAS/CRK/DOCK/Rac.
JNK Rac, Sr178 2, 9. .
12.24 / FAK/ JNK
. Schlaepfer D.D., Mitra S.K., Cur. Opinion Genet Devel, 2004, 14, 92-101.
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Darnall JE, Kerr IM and Stark GR, Jak-Stat patways and transcriptional activation in response
to IFNs and other extracellular signalling pathways, Science, 1994, 264, 1415-1420. DeMali K., Wenerberg K., Burridge K., Integrin signaling to the actin cytoskeleton, Current
Opinion in Cell Biology, 2003, 15, 572-582 Fagerholm S., Hilden T., Gahmberg C., P marks the spot: site-specific integrin
phosphorylation regulates molecular interactions, Trends in Biochemical Sciences, 2004, 29, 504-512
orvath C.M., Stat proteins and transcriptional responses to extracellular signals, Trends in Bioch. Sci., 2000, 25, 496-502
Hynes RO, Integrins: A family of cell surface receptors, Cell, 1987, 48, 549-550 Krauss G., Biochemistry of Signal Transduction and Regulation, Wiley-VCH editions, 2001 Parsons J.T., Focal adhesion kinase: the first ten years, J. Cell Science, 2003, 116, 1409-1416 Quin J, Vinogradova O and Plow E, Integrin bidirectional signaling: a molecular view, PLoS
Biology, 2004, 2, 726-729 Schwartz M.A., Integrin signalling revisited, Trends in Cell Biology, 2001, 11, 466-470 Schlaepfer D.D., Mitra S.K., Multiple connections link FAK to cell motility and invasion,
Current Opinion in Genetics and Development, 2004, 14, 92-101 Schlaepfer DD, Mitra SK, Ilic D. Control of motile and invasive cell phenotypes by focal
adhesion kinase. Biochim Biophys Acta. 2004, 1692(2-3), 77-102. Wozniiak M., Modzelewska K., Kwong L., Keely P., Focal adhesion regulation of cell behaviour,
Biochim. Bioph. Acta, 2004, 1692, 103-119
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