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5/28/2018 11.
1/38
1. MAP s
2.
GPCRs
3. ERK
4. JNKASK1/JNK
JNK Wnt
(Scaffold proteins) JNKJNK
5. S. cereviciaeFus3 ss1
6.
11
5/28/2018 11.
2/38
350
1.
,
. ,
(cAMP, DAG, IP3), (PKA, PKC, CAM-kinase) .
,
, , .
,
, .
(:
), mitogenic
activated protein kinases cascade MAPK cascade.
, . MAPKs
: , , stress .
s
MAPKs ,
. s
s, s.
(MAPK)
(MAPKK)
(MAPKKK)
,
(scaffold proteins). s
S. Cerevisiae, Ste5 Pbs2p. s : 1)
5/28/2018 11.
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351
2)
.
11.1MAP .
. , (scaffold proteins).. JIP-1 JNK.
MAPKs,
.
3 MAPKs ,
,
-:
1. :RafMEK1-2 ERK1-2 (Extracellular signal-Regulated Kinase).
2. (TNF-, UV, ): 1-5, 1, SK1 4,7 JNK (Jun NH2-
terminal Kinase)SAPK (stress activated protein kinase).
3. (TNF-, UV, 22): MEKK4, 1, ASK1 3,4,6p38/HOG.
.
.
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352
ERK JNK/SAPK p38/HOG
TNF-, UV, ILs, stress TNF-, UV, H2O2,
stress
GEF Grb2/hSos - -
GTP-binding protein Ras Rac/Cdc42 -
Raf
MEK1-2
ERK1-2
MEKK1-5, TAK1, ASK1
MEK4,7
JNK SAPKs
MEKK4, TAK1, ASK1
MEK3,4,6
p38/HOG
p62TCF c-Jun, p62TCF, ATF2 c-Jun, CREB, ATF2
11.2 s.
RKs (Extracellularsignal-Regulated Kinases). Ras (
-Ras).
- H Ras ( Raf). Ser/Thr, ,
Ser, (MEK: MAP/ERK Kinase).
- () Thr Tyr,
5/28/2018 11.
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353
-hrXTyr-. MARKK
,
Ser/Thr Tyr.
, (RKs).
- () -hrXTyr-, .
,
.
ERK: Extracellular Regulated
MEK: MAP/ERK Kinase
MEKK: MEK Kinase
11.3ERKs.Ras. H
Ras , Raf MEKK-1.
(). ,
, (
RK1-2). ERK
.
2.
(RTKs),
G (GPCRs) G
G .
-Tyr
, PDGF (platelet derived growth factor)
EGF (epidermical growth factor)
(RTKs),
Tyr. Tyr
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354
SH2 , Grb2
(growth factor receptor binding protein). Grb2 SOS,
, GTP
Ras.GDP, GDP GTP. Ras C-
. Ras.GTP
, Ser/ThrRaf, MAP kinase kinase kinase (MAPKKK).
Raf
, Ser 14-3-3.
Ras,
.
( 2),
Raf,
Raf Ras.
, , ,
KSR,
14-3-3 . 2,
KSR, ERK
. KSR , Raf,
. , Raf KSR-MEK-ERK
(KSR/ Raf-MEK-ERK)
.
11.4 . Raf
KSR , 14-3-3,
[1].
, Ras
(Ras.GTP)
Raf KSR
,
Ras [2]. Anderson D., Role of
lipids in the MAPK signalling pathway, Progress in Lipid
Res. 2006, 45, 102-119.
.Raf. -CR1, Ras-binding domain
(RBD) cysteine-rich domain (CRD). CR2
Ser/Thr,
(D) C-CR3.
a.
[1]
[2]
. Raf
5/28/2018 11.
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356
s
. , RTKs PLC (
9). DAG Ca2+ PKC.
PKC Raf-1 ()
JNK (),
.
11.7 . RTK Ras, Raf. , Raf
MEK/ERK. Tyr
PLC,
PKC. PKC Raf
.
GPCRs
GPCRs
, ,
GPCRs .GPCRs MAPKs.
, , RTKs,
,
, GPCRs MAPKs RTs.
GPCRs, 1, -1,
, , (LPA), -,
(mACh), , 2 ,
PKs,
. GPCRs s
, G .
RTK
/R
Protein Kinase C
-TyrPO4 PLC
RTK
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357
GPCRs
Ks, ,
( COS-7, HEK-293 )
MAPK GPCR . ,
GPCR MAP .:
o (PTX), GiGq, G
.G
G.
o . 3-, GPCR , PI3.
o . 3-, GPCR -,
PI3.
o . 3-, GPCR ,
PI3.
GPCRs MAPKs.
1. trans-RTKs2. 3. PKC
PKs .
12 MAPKs, 7 MAPKKs 14 MAPKKKs, .
G MAPKs
, GPCR
G ,
G
G .
G :
Gs, Gq, Gi, G12. K
.
Gas
, s
,
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358
c
cAMP , Ras-GEF (RAS-guanine nucleotide exchange factor), Epac (exchange protein directly
activated by cAMP).
GRap1,
/ERK. , B-Raf, Rap1 B-Raf,
RK, , , ,
Raf1, Rap1 Raf1,
ERK.
/ -Raf
Raf-1
11.8B-Raf, Rap1 B-Raf, RK, , ,
Raf1, Rap1 Raf1,
ERK. Stork P., Schmitt J., Crosstalk between cAMP and MAP kinase signaling in the
regulation of cell proliferation, Trends in Cell Biology, 2002, 12, 258-266.
, Raf1 : Src, GTP
Rap1, Raf1,
Akt, Raf1 Ser ,
Raf1 Ser,
.
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359
11.9 H Src, GTPRap1, Raf1, Raf1
Ser., Raf1 Akt. Stork P., Schmitt J., Crosstalk between cAMP and MAP kinase signaling in the
regulation of cell proliferation, Trends in Cell Biology, 2002, 12, 258-266.
Gi
s, i cAMP. -
i (gip2) ,
GPCRs Gi s.
Gi-coupled receptors s
G, 3-, Src,
EGF (EGFR).
, trans-
EGFR
. ,
i ,
Rap-GAP,
Rap1 ( GTP),
,
-Raf (
KK)
Raf-1 ( KK),
.
ShcShc
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360
Gq Gq
Ks.
H Gq C (PLC),
- (2) : DAG () IP3
(). 3Ca2+, : CaM kinase II, Ras-GAP (Ras-GTPase-
activating protein) Ras
Raf/MEK/ERK.
C (PKC) ,
DAG.
PKC Raf,
Ras.
C 2(, ). 2 trans-
, Grb-Sos-Ras
Raf/MEK/ERK. C , Src.
Src , Shc, trans- RTK,
Grb-Sos-RasRaf/MEK/ERK
C, ,
, BTK (Bruton tyrosine kinase),
. ,
ERK ,
JNK.
Gq, PLC.
Ras-GAP
PLCPLCGPCRaq
PKC
Raf
MEK
ERK
Shc
Grb
Raf
MEK
ERK
CAM
BTKBTK
PYK2PYK2
IP3/Ca2+
DAG
RasRasSos
SrcSrc
Ras
5/28/2018 11.
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361
G12
,
12Ras-GAP. 12 (pleckstrin
homology) . , 100
, ,
, -
.
p120 Ras-GAP
11.10 p120 Ras-GAP. G12.
, MAPKs
trans-R, Grb-Ss-Ras .
12 Ras-GAP Ras-GAP,
Ras ERK.
, G12
Rho. 12 Rho, Rho-GEF, PTKs, Rho-GEF.
G
G MAPKs
GPCRs, . -
3-.3-:
(. Src), trans- RTKs. RTKs
Grb-Sos-Ras s.
Vav (Rac-GEF), GTPRac. , Rac
JNK.
Ras-GEF (Ras-guanine-specific nucleotide-exchange factor),
Ras MAPKs.
Pro-Pro-Pro SH3 SH2 Kinase
12
SH3SH2 Ras-GAP domain
12
SH2
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362
11.11 , Raf/MEK/ERK.
:
1. RTK, Shc/Sos/Grb2 Ras, Raf//ERK.
2. GPCR, Gs/cAMP/PKA EpaC Rap, Raf Raf-1
Gaq/PLC/PKC Raf-1,
Gaq/PLC/2 tras- RTK
G/ 3 / Src tras- RTK
-/ Src tras- RTK.
.
Marinissen M., Gutkind S., G-protein coupled receptors and signaling networks: emerging
paradigms, Trends in Pharmacol. Sci., 2001, 22, 368-376.
MAPKs GPCRs, G-
GPCRs MAPKs,
G .
1. trans-RTKs GPCRs RTKs GPCRs
.
, proheparin-binding EGF (pro-HB-EGF),
-GF. , -EGF -
GFR, o MAPKs.
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363
HB-EGF
Pro-HB-EGF
Shc
2. -MAPKsGPCRs , .
GPCR- (GRKs)
, , -, AP2 (adaptor
protein-2) . -
G-
.
11.12 (), GPCR G . ()GRKs, -GPCR. ()-GPCR . Lefkowitz R., Whalen E., -
arrestins: traffic cops of cell signaling, Current Opin. Cell Biol. 2004, 16, 162-1168 .
, GPCRs,
-. -COS-,
5/28/2018 11.
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364
s -.
-:
1. Src,
, : ) ,
, ) Ras/ Raf-
MEK-ERK1/2, ) -8.
11.13- Src GPCRs.
: 1)
, 2) Ras ERK1/23) . M. Luttrell and J. Lefkowitz, The role
of b-arrestins in the termination and transduction of G-protein-coupled receptor signals, Journal of
Cell Science 115, 455-465, 2002.
2.-GPCRs,
, -.GPCR / -/ Raf-MEK-ERK
RK . ERK1/2 -
RK1/2.
, ERK -
,
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365
DNA .
11.14-. GPCR , -,
(GPCR/-/Raf-MEK-ERK)
. , ERK , () . M.
Luttrell and J. Lefkowitz, The role of -arrestins in the termination and transduction of G-protein-
coupled receptor signals, Journal of Cell Science 115, 455-465, 2002.
, ,
-,
.
Raf-MEK-ERK, - KSR
, - .
-, 1 (MEK partner 1),
p14, ERK (Raf) .
,
.
11.15
(KSR),
(-)
(1). Anderson D.,Role of lipids in the MAPK signalling pathway,
Progress in Lipid Res. 2006, 45, 102-119.
5/28/2018 11.
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366
3. ERK
1.ERK .
ERK . ,
,
(early response genes). EGF PDGF, .
c-fos, c-myc
c-jun,
.
c-fos, SRE (serum response element),
p62TCF p62SRF
. ERK p62TCF
p62TCFp62SRFSRE, c-fos.
, c-Fos c-Jun,
(-1, activator protein complex), .
(1)
ERK
11.16 (c-fos) RK. EGF
GTPRas. (ERK) ,
p62TCF
. O p62TCF
, p62SRF
,
c-fos, .
Gomberts B., Kramer I., Tatham P., Signal Transduction, Elsevier, 2002.
5/28/2018 11.
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367
2.ERK .
mRNA. ERK
.
5 mRNA,
40S, mRNA, , eIF-4E. eIF-4E
mRNA
eIF-4G, eIF-4A eIF-4, mRNA 40S
. ERK eIF-4E,
, MNK-1 (MAP kinase integrating kinase-1),
ERK, eIF-4E,
mRNA.
ERK:
11.17 RK. ERK -1,
eIF-4E.
(eIF-4G, eIF-4A, eIF-4B) -mRNA,
mRNA 40S .
Gomberts B., Kramer I., Tatham P., Signal Transduction, Elsevier, 2002.
3. ERK .ERK
, , , .
,
HGF (hepatocyte growth factor) c-Met Raf-1. ERK
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368
yr118 Src. ERK
Ser83,
FAK (focal adhesion kinase). FAK :
3- GTP Rho , Rac,
, FAK
, .
11.18 ERK FAK. . ,
HGF c-Met Src Raf
ERK. ,
. Kolch W., Coordinating ERK/MAPK
signaling through scaffolds and inhibitors, Nature Reviews, Mol. Cell Biol., 2005, 6, 827-838.
4.ERK. ,
ERK, -1, ERK . .
-1 (kinase phosphatase-1) ,
11.19 ERK , ,
MKP-1, ERK.. Gomberts B., Kramer I., Tatham P., Signal Transduction, Elsevier, 2002.
5/28/2018 11.
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369
4. JNK
JNK (c-Jun NH2 terminal kinase, 2-
c-Jun) stress, , - ( -1 TNF-
tumor necrosis factor), stress (, , pH), Ca2+, SAPK (stress-activated
protein kinase).
stress [1-5, -1 (TGF- activating kinase),
ASK-1 (apoptosis signal-regulatory kinase)],
(4,7), JNK1-3 (. 11.20).
, JNK
c-Jun (). c-Jun c-Fos
Ap-1 (Activator protein 1). Ap-1
, ,
, . c-Jun,
JNK, (F2, p53 ). JNK
(16, ), JNK
.
-PO4-PO4 AP-1
11.20stress (TNF) JNK. JNK c-Jun -1. -1 (c-Jun + c-Fos) DNA (TRE)
, ,
.
ASK1/JNK
JNK
ASK1(apoptosis signal-regulating kinase 1). ASK1
Ser/Thre, ,
2
2,
GPCRs,
Ca2+. ,
Stress/(TNF)
1-5, 1, SK1 ()
4,7 ()
JNK1-3 ()
c-Jun
c-Fos
TRE: TPA Responsive Element (DNA binding element)
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ASK1 4/7 3/6,
JNK .
SK1 , C-
coiled-coil . ,
, , 14-3-3
rx, . ASK1, ,
Thr (Thr845 , Thr838 )
.
11.21 ASK1. Matsukawa J., Takeda K.,Ichijo H., The ASK1-MAP kinase cascades in mammalian stress response, J. Biochem., 2004, 136,
261-265.
ASK1. ROS
(reactive oxygen species) ( 22)
, ,
.
22 Trx, ASK1 . ROS
ASK1/JNK: TNF (tumor necrosis
factor) TRAF2 (TNF receptor associated factor 2)
GPCR .
, TNF,
.
ASK1.ASK1/JNK
.
Ser/Thr , IRE1, ASK1, TRAF2.
, Huntington ,
huntingtin Q .
ASK1/JNK .
Ca2+ASK1.Ca2+
Ca2+-RK
. -
I(CaMKI) ASK1/p38,
.
ASK1. Fas,
SK1
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371
FasL : FADD
8, Daxx, -
ASK1 JNK (16, ).
11.22ASK1 .ASK1 Trx,
. ROS F
GPCR, Trx, ASK1
. ASK1 Ca2+
,
CaMKII,
. ASK1
JNK . Matsukawa J., Takeda K., Ichijo H., The ASK1-MAP
kinase cascades in mammalian stress response, J. Biochem., 2004, 136, 261-265.
GPCR JNK.
JNK GPCRs.
G13
JNK, , ASK1, 4/7,
JNK. , GPCRs Gq G13
JNK Rac/Cdc42
(. 11.23).
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372
11.23GPCRs JNK. GPCRs GqG13JNK Rac/Cdc42
. G13JNK,
, ASK1, 4/7,
JNK.
JNK Wnt
Wnt/Wingless
, ,
.
. ,
Wnt .
Wnt Wnt
Frizzled (11.24). Wnt,
Frizzled : Wnt JNK. ,
Dishevelled.
Wnt, Dishevelled
GSK3, -, Axin, APC (adenomatous polyposis coli).
-,
TCF, , c-myc
cyclin-D1. , Dishevelled GTP
Ras, Rho, JNK,
.
Wnt
. PAR-1 Naked.
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11.24 () -() Wnt.
Frizzled (Fz)
Dishevelled (Dsh),
3 (DIX,
PDZ, DEP). DIX PDZ
Dsh,
Wnt DEP
Wnt (JNK).
Dsh,
.
PAR-1 Naked,
Wnt,
JNK. Weston & Davis, Current
Opinion in Genetics & Development
2002, 12: 14-21.
PAR1: Dishevelled - PDZ . Wnt
PAR1 Wnt
upstream -Axin.
PAR1 JNK Dishevelled,
.
Naked: Wnt/ - JNK. naked
downstream Wnt-1 upstream -
PDZ Dishevelled.
(Scaffold proteins) JNK
( )
JNK.
,
JNK Crk II, , -
JIP:
Crk II (adaptor protein): - SH-3 Crk II
- JNK.
JNK Rac1 (G-
).
() ()
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374
(280):, . MKK4,
MKK7 JNK.
-: --1 -2. --2
JNK, ASK1, MKK4 JNK3.JIP: JIP MLKs (mixed-lineage protein kinases)
MKK7 (11.19). JIP JIP1
JIP2 ( 1 2 ). JIP
. ,
JIP1 -,
.
JNK,
.
JNK
JNK (Jnk1, Jnk2, Jnk3). Jnk1Jnk2
, Jnk3 .
knockout Jnk1, Jnk2Jnk3(
) ,
.
Jnk1Jnk2,
.
11.26
(exencephaly),
,
.
11.25 H JIP-1 (scaffold protein) JNK.
JIP-1 MLK7,
JNK.
www.le.ac.uk/bioche/research/md38_r.html.
5/28/2018 11.
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375
- 4, 7,
.
, JNK .
4 7 JNK.
stress, 4 7
JNK Tyr Thr , JNK.
- knock out ,
JNK. ,
(MEKK1-4) JN.
MEKK1 ,
,
JNK, MEKK3 .
: JN, , , .
JNK .
JNK. (CrkII, , --2,
JIP2 JIP3) MAPKKK JNK (MLK, ASK2,
MEKK2, MEKK4 TAK1). ,
.
JNK
.
5. S. cereviciae
, .
,
.
,
,
, ,
, .
s (mitogen activated protein kinases)
. , 5
s
(mating), (invasive
growth), o,
, .
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376
11.27
.1. Fus3 .
2. Kss1, .
3. Hog1, .
4. shock Mpk1,
.
5. C N Smk1, .
5/28/2018 11.
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377
.
, Saccharomyces cerevisiae
. ,
a .
(
): , a , a a
.
, ,
(Ste11/Ste7/Fus3).
GPCR
G-,
Ste5 . , ,
Ste20, Ste11 (MAPKKK),
Ste7 (MAPKK),
MAPKs Fus3Kss1. Fus3 Kss1
Ste12, (11.28). s Far1,
.
11.28 (a mating factor) S. cerevisiae.GPCR G . G
Bem1, GAP , G (Cdc42 Cdc24),
Rho
, (morphogenesis)
. , (Ste11,
Ste7, Fus3/Kss1), Far1
Fus3 , , Ste12 .
5/28/2018 11.
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378
11.29 Saccharomyces cerevisiae., .
a .
:
, a , a a
.
. ,
, .
a
a
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STRESS .,
,
stress:
(pseudohyphal growth) ,
(invasive growth) , .
, Ste20, Ste7, Ste12 Ste11,
Ste5, . ,
, MAPK
, , ,
.
, mating/filamentous
.
11.30 (sexual conjugation/invasive growth/filamentous growth)MAPK .,
. ,
(invasive growth). , , .
Ashton Breikreutz and Mike Tyers, MAPK signaling specificity: it takes two to tango, Trends in
Cell Biology, 2002.
Low nutrient
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11.31 Saccharomyces cerevisiae. (Yeast-forming growth). H
(pseudohyphal growth) ,
,
(hyphal growth). Graeme M. Walker, Yeast, Physiology and Biotechnology, 2000.
11.32 H. www.Yeastgenome Org/yeast-
images.shtml.
Fus3 Kss1
(mating)
.
s (Fus3 Kss1). , s
.
. Fus3
Ste5, Kss1
, .
Fus3 ,
Kss1 , Far1,
Fus3. Far1
5/28/2018 11.
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381
. , Fus3
.
Fus3 Kss1 , , Kss1
,
Fus3, .
, mating/filamentous , .
Fus3 Kss1.
.
, Fus3 Ste5,
Kss1 . ,
Fus3 Far1, Kss1, in vivo
in vitro. , Kss1
Fus3.
11.1
s -, .
Garington T. and Johnson G., Organization and regulation of mitogen-activated protein
kinase signaling pathways, Current Opinion in Cell Biology 1999, 11, 211-218.
5/28/2018 11.
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382
6. s
,
, ,
. , MAP
. , , ,
, , . s
, ,
.
Arabidopsis
thaliana 60 s, 10
s 20 s.
11.33 s . . ,
Arabidopsis, (alfalfa) , , (
), stress, , s.
Tena G., Asai T., Chui W., Sheen J., Plant mitogen activated signaling cascades, Curr. Opin. Plant
Biol., 2001, 4, 392-400.
. ( , , ).
5/28/2018 11.
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383
() ,
, ,
.
s.
, .
,
.
.
.
stress.
.
. ,
. -
AtHK1 (Arabidopsis thalianaHistidine Kinase 1),
(AtMEKK1-AtMKK1/2-AtMPK4).
,
.
, ROS,
.
.
. Arabidopsis,
(flg22) FLS2 MEKK1-MKK4/5-
MPK3/6 .
,
,
- . -
-
.
. NtNPK1-
NtMEK1-Ntf6. 1 ,
NACK1 (NPK1-activating kinase like protein1)
, .
NACK1 1 .
G2, 1
, CK1/2 . CK1
- (CDK) , 1. , CDK
1. NACK1/2
5/28/2018 11.
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384
1 .
, CDK 1
NACK1.
. 1 .
G1, NACK1 1 .
11.3 4 1, . 1G2 , .
(), 1
NACK1. CDK
. CDK , 1
, NACK1 . Jonak C., Okresz L.,
Borge L., Hirt H., Complexity, cross talk ant integration of MAP kinase signaling, Current Opinion in
Plant Biology 2002, 5, 415-424.
Anderson D., Role of lipids in the MAPK signalling pathway,Progress in Lipid Res. 2006,
45, 102-119.
Breikreutz Ashton and Mike Tyers, MAPK signaling specificity: it takes two to tango, Trends
in Cell Biology, 2002, 12, 254-257.
Garington T. and Johnson G., Organization and regulation of mitogen-activated protein kinasesignaling pathways, Current Opinion in Cell Biology 1999, 11, 211-218.
Graeme M. Walker, Yeast, Physiology and Biotechnology, 2000.
Jonak C., Okresz L., Borge L., Hirt H., Complexity, cross talk ant integration of MAP kinase
signaling, Current Opinion in Plant Biology2002, 5, 415-424.
Kolch W., Coordinating ERK/MAPK signaling though scaffolds and inhibitors,Nature
Reviews, Mol. Cell Biol.,2005, 6, 827-838.
Kraus S., Naor Z., Seger R., Intracellular signaling pathways mediated by the GnRH receptor,
Arch. Med. Res.,2001, 32, 499-509.
Lefkowitz R., Whalen E., -arrestins: traffic cops of cell signaling, Current Opin. Cell Biol.
2004, 16, 162-1168.
Lefkowitz R., Shenoy S., Transduction of Receptor Signals by -arrestins, Science2005, 308,512-517.
5/28/2018 11.
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385
Liebmann C., Regulation of MAP kinase by peptide receptors signaling pathway: Paradigms
of multiplicity, Cellular Signalling, 2001, 13, 777-785.
Lowes V., Ip N., Wong Y., Integration of signals from receptor tyrosine kinases and G-
protein-coupled receptors,Neurosignals, 2002, 11, 5-19.
Luttrell LM and Robert J. Lefkowitz, The role of -arrestins in the termination and
transduction of G-protein-coupled receptor signals,Journal of Cell Science 2002, 115,455-465.
Matsukawa J., Takeda K., Ichijo H., The ASK1-MAP kinase cascades in mammalian stress
response,J. Biochem.,2004, 136, 261-265.
Naor Z., Benard O., Seger R., Activation of MAPK cascades by G-protein-coupled receptors:
the case of GnRH receptor, TEM, 2000, 11, 91-99.
Park HS, Huh SH, Seo JS, Choi EJ Hsp72 functions as a natural inhibitory protein of c-jun
N-terminal kinase.EMBO J.2001, 20:446-456.
Putcha GV, Moulder KL, Golden JP Induction of BIM, a proapoptotic BH3-only BCL-2
family member, is critical for neuronal apoptosis.Neuron2001, 29: 615-628.
Rincon M, Davis RJ, Flavell RA Signal transduction by MAP kinases in T lymphocytes.
Oncogene2001, 20, 2490-2497.Shenoy S., Lefkowitz R., Multifaceted roles of -arrestins in the regulation of seven-
membrane-spanning receptor trafficking and signaling, Biochem. J., 2003, 375, 503-
515.
Stork P., Schmitt J., Crosstalk between cAMP and MAP kinase signaling in the regulation of
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