o

1.





-
Ras

2.

SH2
P,
SH3

PDZ
WW

3.
4.
P

Glut4

264
, /
.

.
, ,
. 9.1
,
.

,
:

.
.
,
.

.

,
,
.
.
a. Tyr

.
Tyr

9.1
. )
,

(effector proteins).
. )
, ,
.
.

265
9.1 :

PDGF (platelet derived growth

factor):

PDGF : AA, AB

,

(17kD) (16kD)


c-sis
-

,
PDGF-Ra (170kD) PDGF-R (180KD)

EGF (epidermal growth factor):

TGF-a (transforming growth

factor):
- a

6kD, o EGF
TGF-a 40%

. EGF-R
c-erbB -

TGF- :
-
TGF-1, -2, -3

25 kD

TGF-RI &
Ser/Thr

IGF-1 IGF-2 : Insulin-like

7 kD,
-

IGF-R

FGF-1, FGF-2, FGF-3, FGF-4:

16-32 kD

G-CSF : Granulocyte colony

stimulating factor

24 kD

150 kD, G-CSF

GM-CSF : Granulocyte
macrophage-colony stimulating
factor

14 kD

51 kD, GM-CSF

1-7 (IL-1 IL7), 9, 12, 15 (IL-9, IL-12,

IL-15)

(IL-R-1- IL-R-7)

-8, IL-8

IL-R-8. G

Epo-R,

TNF: Tumor necrosis factor

TNF-R,

LIF:

LIF-R,

,,

INF-Ra, INF-R, INF-R,

266
1.
,
.

.

.
.

. ,
,
, , .

,

( 9.1).
-.


,
.
100
.

( 9.2 9.3).

9.2


.
5
:
1. EGF-R (
)
2.
()
3. PDGF-R (
)
4. FGFR-R (
)
5. TRKA (
).
Ullrich
and Schlessinger (1990).

267

9.3
. Hubbard SR and Hill JH., Protein tyrosine kinase structure and function,
Annu. Rev. Biochem., 2000, 69, 373-398

, -
: ( EGF, NGF, PDGF )
( ).
/
,
. (
) ,
(
) .
, ,
.
H EGF.
,

H PDGF.
5 ( )
(immunoglobulin-like domains).

,
(kinase insert region).
, -.

268

9.4
PDGF (
).
.

. -
,
, GAP (GTPase activating
protein), 3- C- (PLC). 85
/ -
-. W.J. Fantl et al, Annu. Rev.
Biochem., 1993, 62, 453-481.

FGF (fibroblast growth factor:

).
3 ,
( ).
.
NGF (nerve growth factor:
). NGF (neurotrophins)
neurotrophin receptors family.
trk, trk trkA. 2
(Ig-like domains) 2
.
/ -

. - -,
S-S 22.
(-precursor),
Golgi,
, ,
.
- ,
. 15-20
, . -
.
,
-, -
.
-
, .
.

269

Cys

9.5


.





.

( 9.12).
,
. ,
.
,
- . ,
-
S-S. ,
.

,
.

(multivalent), (
)

.

270

9.6
(hGH)

, EGF, hGF o
FGF ,

.

(hGH),
217
( 9.6).
638 .
.

.

( 9.7).

hGH

GH

9.7 (hGH, Growth Hormone)

(GH-R). 4 -,
. hGH
, GH-R, .

()

9.8
. Berg et al, ,
, 2004.

271
(FGFs)
21 (FGF1-21) 4
FGF (FGFR1-4)
. FGFs ,
, .
FGF-Rs
.
()

()

FGF(1-21)

()

9.9 (FGF)
. , ,
. () FGFR. () FGF,
(
, ). Voet and Voet, Biochemistry, 2004.

EGF

9.10


. EGF
,
EGF-R.
,
EGF
. ,
.
Molecular Cell Biology, Lodish et al, 2007.

272
,
. PDGF
,
.

9.11.
.
.

S-S

- ,
, .
,
.

. ,
.
9.12
PDGF.
,
.

,

.

.

273

9.12 - - PDGF.
PDGF, - -, ,
.
(PDGF: platelet derived growth factor)
, ,
, .
, ,
PDGF .

.
.
,
,
.
:
, trans- .
(protomers)
,
( 9.13).

274

9.13
.
-
/
.

)
.

)
(bivalent ligand)
,
.

. -

. -

9.14 (L, ligand)

.
.
/ .
( SH2
PTB), ,
.

275

.

(Hubbard et al., 1994).
22 ( 9.15). -

. ,
.
-
7 .
,
.
. ,
IRS (insulin receptor substrate),
,
SH2 .

.
306

Ser/Thr.
: .
Arg,
.
, ,
Tyr . ,
(Tyr1162 9.14),
. .
, Tyr1162

ATP. .

. ,
, ,
ATP .
,
( ).
Tyr1162 .

.

.
trans- -,
.
Tyr1162 .

276

Tyr1162.

9.15 .
. P-
ATP.
Asp Asn,
Tyr Ser/Thr.
Tyr
(Tyr1158, Tyr1162 Tyr1163).
.
-

.
-
: trans-
(-) Tyr,
. , Tyr
.
, SH2 PTB . (effector
proteins: )
- (adaptor
molecules),
.

( 9.16).


.

277
-
SH2
.
,

. 9.16 -
, PDGF
.

- C
- Tyr:
Src
- p120 GAP
-
Grb2
Shc
IRS
- Tyr:
Syp
- -3-

9.16 trans .
, SH2 ,
.
, -.

: C, (src ..), p120 GAP ( GTP activating protein),
- (Grb2, Shc, IRS), (Syp .) 3-.

- :
- p85 PI3-
- C
- Src
- p120 GAP, GTPase (GTPase activating enzyme),
Ras
- Grb2 , - (adaptor protein) Ras-

- SH2-PTP2 .

.

278
,
,
(inositol-1,4,5-triphosphate, IP3), (PtdinsP3), Ca2+,
(diacylglycerol, DAG).

. - ,
- ,
,

581

-P

Src

- P Grb2 SOS

9.17
PDGF
SH2
.

.
PDGF

. 9

.

SH2
:
Src: .
Grb2, p85: , PI3-kinase:
3--,
GAP: GTPase activating protein,
PL-C : C.

9.18 PDGF EGF

.

279

. :
-

, . C-
, . PI3
. Grb2-Sos, Shc-Grb2
Ras

-
Ras, G-,
.
- Grb2, SH2
. Grb2 SH3
Sos ( GEF, Guanine nucleotide
exchange factor). Sos GDP GTP
GTP Ras.

GDP

Ras

Pro,
Ras

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Adaptor molecule

Ras

9.19 RTK (Receptor Tyrosine Kinase), , GRB2 SH2 Tyr

SH3 Sos, ,
GTP Ras. Alberts et al, Essential Cell Biology, 1998.

2.


. ,
,
,
, ,
.

280

.
(domains) 60-100 ,
.
.

.
, : /

/
.
-.
- (multivalence of signal proteins),

,
.
,
, :
SH2 PTP :
.
SH3: .
PH (Pleckstrin Homology) :
.
PDZ :
.
WW :

.
9.20

.
Src/Lck:

Tyr
Syp:
.
p85/PI3K:
3
Grb2, Shc, IRS-1:

Stat:

ARK: .

281

9.21


.

PH, SH2, SH3
PTB. SH2
PTB

1
2. SH3

3,

-
.
3

.
SH2

SH2
.
Src .
SH: Src homolog. Src ( sarc)
. ,
, (v-sarc) .
(c-sarc)
.
SH2
SH2 -
.
.
SH2

SH2.
SH2.
.

SH2,
5 (1A, 1B, 2, 3, 4)
.
,
, PTB (phosphotyrosine binding domain).
SH2
SH2 ,
SH2 ,
,

282
. ,
SH2 .
. ,
Syp, SH2, Tyr
PDGF, -
Grb2, SH2 .
SH2
,
( SH2 ),
. PI3-
C. .
, ,
Src. Src
, SH2 . -
(Y527) Src,
. Tyr
(pY527) SH2 ,
. SH2
, - Src .

527

COOH

9.22 Src .
(Tyr527),
Src . Tyr527( P-Tyr527)
SH2 , Src.
: 1.
SH2 Src, Tyr527.
Src
SH2 . SH2 SH2 Src
P-Tyr527. 2. P-Tyr527
. 3. S3 .

283

9.23 c-Src 527.

Src .
: i) Tyr 527
SH2
ii) SH3 SH2
.
.
PTB,

SH2

.
Shc,
SH2, IRS1 (insulin receptor
substrate). PTB
.
, SH2 PTB . PTB
PH .
SH3

.
.
SH3
, 10 .
.
SH3
SH3
,
II,
.

284
X-P-p-X-P
SH3. (P) , X
p
. ,
(pocket) SH3 .
CN NC. SH2 ,
SH3 ,
,
.
SH3
SH3 SH3
Abl Src,
(tumor-transforming potential)
.
SH3
. SH3
:
1. :
SH3
, . SH3

. -
Ib. SH3
Ras .
2. :
SH3 Src
SH3 , .
3. :


.
SH3
( 9.15).
- Crk, Grb2 Nck Abl
. - SH3
Abl .

.
SH3
.
SH3
.
,
,
.
. , ,
. ,
SH3 . SH3

285
, ,
, , .
Pro riche

SH3 domain

9.24 SH3 . SH3

S1

. ( S2),
SH3
, .
(Pleckstrin Homology Domains)

PH 100
, Ser/Thr, ,
C (PL-C, ), G (G
nucleotide exchange factors), -,
. PH 47 kDa, ,
C .
PH -

. PH PLC1 ,
Ptd(Ins)P2, . PLC1
Ptd(Ins)P2
PTB .
.

9.25 C ,
.

286
, PH (anchoring
functions) ,
.
,
.
PDZ

PSD-95,
DlgA ZO-1. ,
(. )
. PDZ
,
E(S/T)DV .
PDZ
. PDZ
, ,

.
PDZ
. ,
PDZ
. lnaD Drosophila,
, 5 PDZ
-.
- Drosophila.
C-, Gq
, TRP C. o
TRP C,
. , C
, , TRP .
lnaD -
, .

9.26 InaD PDZ (5 PDZ )

,
, , PLC, PKC Trp.

287
WW
35-40 ,


. WW
. .

. H WW - cis trans
Pin1 ,
, Pin1
in vivo.
3.
,
,
,
.
- (adaptor proteins)
. -
, , .
,
,
. , -
.
,
.
,
-.
,
, ,
- .
c-Crk II
Grb2
IRS-1
Shc

9.27 -.
,
. IRS-1: , :
, : , : SH2
, .

288


.
, ,
Ser Tyr. ,
SH2
- .
Grb2 (growth factor receptor binding protein)

Ras. Shc, EGF, PDGF
Syp, SH2
Grb2. Grb2 , SH3 ,
G, Sos,
Ras. Grb2-Sos,
Grb2
Ras. Sos
Ras.
Crk - -
CT10 ASV-1. SH3 Crk Alb,
Crk .
, IRS (insulin receptor substrate)
- .
, . IRS
,
, Grb2-mSos, 3-,
SHP-2. IRS
, -
, ,
.
4.

,
.
(
,
microdomains, )
( , .

).

.
,
- .
: ) )
, ,

289
.
(
)
, .
,
, ,
,
.

.

.
,

.

.

9.28
.
( )
, .
Molecular Cell Biology, Lodish et al, 2000.

,
, .
.
,

290
(IRS, APS, c-Cbl , Gab-1, Shc).

SH2,
.

9.29

(IRS1-4, APS,
Shc, Gab-1)
Trends in Cell Biology 2002, 12,
65-71.

IRS, ,
,
.
IRS , ,
PI3-K ( 3-). 3-
, (p85)
(p110). p110 PIP2 (4,5 ) PIP3 (3,4,5 /). PIP3
- (PDK1),
(Akt) C (PKC)
,
, ,
.

9.30 ,
. IRS .

291
Glut4

-
Glut4. , Glut4
, trans-Golgi .
Glut4 .
Glut4 . Glut4
( 9.30). Glut4
- .
Glut4 .
.

Glut1

Glut4

,


,

9.31 Glut4.
() Glut4 -
. ()
. ()
. Molecular Cell Biology, Lodish et al, 2000.

,
GTP- Glut4

292
PI3-. PI3K
PIP2 3 PDK1 PKC
Akt Glut4 ,
, PI3-.
,
(caveole), , .
, APS (adaptor
protein substrate) SH2
Cbl . Cbl CAP (Cbl
associated protein), ,
.
Cbl ,
CrkII. CrkII GEF C3G,
GTP TC10,
(
9.29).

, ,
,
.

,
1
/ GSK3.
,
PIP3 (3,4,5 ),
Glut4
.

Alberts A., D. Bray, A. Johnson, J. Lewis, M. Raff, K. Roberts, P. Walter: Essential Cell
Biology, 1998, 549-550
Berg JM., Tymoczko JL., Stryer L, (K 15),
, 2004
Fantl W.J., Johnson D.E., Williams L.T., Signalling by receptors tyrosine kinases, Annu. Rev.
Biochem., 1993, 62, 453-481
Hubbard SR., Wei L., Ellis L., Hendrickson WA., Crustal structure of the tyrosine kinase
domain of the human insulin receptor, Nature, 1994, 372, 746-754
Hubbard SR and Hill JH., Protein tyrosine kinase structure and function, Annu. Rev.
Biochem., 2000, 69, 373-398
Saltiel Alan R. and Jeffrey E. Pessin: Insulin signaling pathways in time and space, Trends in
Cell Biology, 2002, 12, 65-71
Krawss Gerhard, Biochemistry of Signal Transduction and Regulation, Wiley Eds
Ullrich A. and Schlessinger J., Signal transduction by receptors with tyrosine kinase activity,
Cell, 1990, 61, 203-212