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第三章. 细胞信号转导的分子机制. The Molecular Mechanism of Cellular Signal Transduction. 细胞的社会性. 外界环境变化时. 单细胞生物 —— 直接作出反应. 多细胞生物 —— 通过细胞间复杂的信号传递系统来传递信息,从而调控机体活动。. 生物体内各种细胞在功能上的协调统一是通过细胞间相互识别和相互作用来实现的。一些细胞发出信号,而另一些细胞则接收信号并将其转变为自身功能变化,这一过程称为 细胞通讯( cell communication ) 。

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第三章

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The Molecular Mechanism of Cellular Signal Transduction


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  • cell communication

  • signal transduction


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The General Information of Signal Transduction


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()

target cell

()

()


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gap junction


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  • chemical signaling


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endocrine

paracrineautocrine

neurotransmitter


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  • TB


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  • receptor

  • ligand


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19-1


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-


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  • signal transduction pathway


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  • cross-talkingsignal transduction network


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RNA

RNA

NH2

m7G

AAAAA

Translation


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Intracellular Signal Molecules


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  • signal transducer


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cAMPcGMPDAGIP3-3,4,5-PIP3Ca2+second messenger


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  • cAMPcGMP


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  • cAMPcGMP


1 camp cgmp

1. cAMPcGMP

adenylate cyclaseAC

guanylate cyclaseGC


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2.

  • phosphodiesterasePDE

  • cAMPPDEcAMPcAMP

  • PDEcAMPcGMP


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3

  • cAMPcGMP


A camp

AcAMP

  • cAMPcAMPcAMP-dependent protein kinasecAPKAprotein kinase APKA

  • PKA


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cAMP PKA


G cgmp

GcGMP

  • cGMPcGMPcGMP-dependent protein kinasecGPKGprotein kinase GPKG

  • PKGPKAPKGPKG


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cGMPPKG


4 camp cgmp

4cAMPcGMP

  • cAMPcGMP

  • cGMP-

  • -


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  • diacylglycerolDAG

  • arachidonic acidAA

  • phosphatidic acid PA

  • lysophosphatidic acidLPA

  • 4-PI-4-phosphatePIP

  • -4,5-(phosphatidylinositol -4,5-diphosphatePIP2)

  • -1,4,5-Inositol-1,4,5-triphosphateIP3

  • :


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  • PI-3KPI-4KPI-5K

  • C PLC-4,5-PIP2DAGIP3


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PLA1

PLD

PLA2

PLC

PLC

3

2

1

4

A

6

5

-1235--46-


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2

  • DAG

  • IP3


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IP3 IP3

IP3

  • IP3IP3


Dag c

DAGC

  • Cprotein kinase CPKC/

  • PKC

  • PKC12


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DACPKC

DAG

Ca2+

DAG

Ca2+


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1

  • 1.12~1.23mmol/L

  • 90%Ca2+0.01~0.1mol/L


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  • Ca2+

  • Ca2+Ca2+-ATP


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2

  • calmodulinCaMCa2+

CaM

Ca2+

Ca2+

Ca2+

CaM

Ca2+

Ca2+


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Calmodulin, contains four high-affinity Ca2+-binding sites. The binding of Ca2+ induces a conformational change in calmodulin. One of the many enzymes regulated by calmodulin and Ca2+ is Ca2+/calmodulin-dependent protein kinase, which phosphorylates Ser and Thr residues in target proteins.

Ca2+

Ca2+-

A ribbon model of the structure of calmodulin, determined by X-ray crystallography. The four Ca2+-binding sites (red) are shown occupied by Ca2+ (yellow).


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  • CaMCa 2+/CaM-CaM-K

:

:

2:

CaM-K

Ca2+/CaM- I

CaM-K

Ca2+/CaM- II


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3

  • Ca2+PKCACcAMP-PDE


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+

NH2

H2N

NH

+

COO-

H2N

O

H2N

NH

+

COO-

H2N

NO

  • NONO

NO

NO


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NO

.

GTP

cGMP

cGMP

  • NOADP-


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  • NOcarbon monoxideCOsulfureted hydrogenH2S


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    • CDPLD

    • /


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/

  • protein kinaseprotein phosphatase


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Thr

Ser

Tyr

Thr

Ser

Tyr

-OH

ATP

ADP

-O-PO32-

Pi

H2O


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1. /

  • ATP -800


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2.

  • (phosphatidase)


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PTK

PTP

PTP

P

PTK

Src

family

PTK

Src family

PTK

P

P

S

S

PTK

PTP


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  • /

  • /


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/

  • /

    • PKAPKG

    • DAG/Ca2+PKC

    • Ca2+/CaMCa2+/CaM-PK

    • PIP3PKB

    • mitogen activated protein kinase, MAPK


1 mapk

1. MAPK

  • MAPK

  • extracellular regulated kinaseERK

  • c-Jun N -/c-Jun N-terminal kinase/stress-activated protein kinaseJNK/SAPK

  • p-38-MAPK


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  • ERKERK

  • JNK/SAPK

  • p38-MAPK


2 mapk

2. MAPK

  • MAPKMAPKKMAP kinase kinaseMAPKKKMAP kinase kinase kinase

  • MAPKKMAPK

  • MAPKKKMAPKKKMAPKKMAPK


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MAPK

MAPKKK

P

P

MAPKK

Thr

Tyr

Thr

Tyr

MAPK

MAPK

phosphatase

on

off


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  • MAPK

  • MAPK

  • MAPK


Erk raf mek mapk

RafMAPKKK

MEKMAPKK

ERKMAPK

ERKRaf-MEK-MAPK

  • ERKERK1ERK2ERK3

  • ERK


Jnk sapk

MEKKMAPKKK

JNKKMAPKK

JNK/SAPKMAPK

JNK/SAPK()

  • JNK/SAPK


P38 mapk

apoptosis signal regulating kinase 1ASK1

MAPKKK

MKK3/MKK6MAPKK

P38-MAPK

P38-MAPK

  • P38-MAPK


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  • Protein Tyrosine kinasePTK

  • TB


1 ptk

1. PTK

  • PTK

  • PTK

  • PTKSH2


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PTK

PTK

HGFR

EGFR

IGFR


2 ptk

2. PTK

  • PTK

  • PTK


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PTK


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  • JAKjust another kinasejanus kinase

  • Src(Rous sarcom)


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  • G


G gtp gdp

GGTP/GDP

  • guanine nucleotide binding proteinG proteinGGTP

  • GTPGDPG

  • GTP

  • GGTPGTPGDP


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  • G

  • G7G(G)

  • G21kD


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GG

GDP/GTP

GTP

G

(G)


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  • GGG protein-coupled receptorsGPCRsPLC


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2. G

  • G21kD

  • RasGRas

  • Ras50


Structure of ras with gdp

Structure of Ras with GDP


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  • G

  • guanine nucleotide exchange factorGEFguanine nucleotide release proteinGNRP

  • guanine nucleotide dissociation inhibitorGDIGTPGAP


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1.

  • signaling complex

  • protein interaction domain


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SH2

PH

SH3

Btk

TH

SH2

SH3

SH3

Grb2

stat

SH2

DNA

TA

PTB

SH2

tensin

//


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Pleckstrin Cplatelet and leukocyte C kinase substratekstrKSTR


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SH2


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SH3


Ph pleckstrin homology domain

PH(pleckstrin homology domain)

  • G ,


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2.

  • adaptor protein

  • 22


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2014112731


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3.

  • scaffolding proteins


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Signal Pathways Mediated by Different Receptors


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G-


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  • DNA

  • D


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  • -

  • Hsp90DNA-

  • -

  • -


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  • -ligand-gated receptor channel


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  • -


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Ion-channel linked receptors in neurotransmission


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GG

  • GGPCRGG

  • GGPCR


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  • GPCRserpentine receptor


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Alfred G. Gilman

Martin Rodbell

  • G1994


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G

+

G


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G


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  • GACPLCeffector

  • ACGss stimulateiiinhibit


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G


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G


1 camp pka

1. cAMP-PKA

  • cAMPPKA

  • PKA/


1 camp pka1

1. cAMP-PKA


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1


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Glycogen breakdown in skeletal muscle


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2


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3

  • PKA


2 ip 3 dag pkc

2. IP3/DAG-PKC

GPLC

PLCPIP2DAGIP3

IP3Ca2+Ca2+

Ca2+PKCDAGCa2+PKCPKC


2 ip 3 dag pkc1

2. IP3/DAG-PKC

  • PKC

  • PKC

  • PKC


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Phorbil ester()

AP1Fosc-jun

PKC


3 ca 2

3. Ca2+/

  • GCa2+

    • G

    • PKACa2+

    • IP3Ca2+


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  • Ca2+

  • Ca2+/CaMCa2+/CaM

  • / MLCKPhKCal-PK


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  • 1


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  • -

  • -


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  • MAPK

  • JAK-STAT

  • Smad

  • PI3K

  • NF-B


1 mapk1

1. MAPK

  • MAPKMAPKMAPK

  • MAPK12ERKp38 MAPKJNK


Ras mapk

Ras/MAPK

  • epidermal growth factor receptor, EGFRPTK

  • Ras/MAPKEGFR


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EGFR


2 jak stat

2. JAK-STAT

  • JAKJanus kinase

  • JAKsignal transducer and activator of transcriptionSTATJAK-STAT


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  • JAK

  • JAKJAKSTAT

  • STATSTAT

  • JAKSTATJAKSTAT


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  • IFN-JAK1/JAK2-STAT1

    IFN-

    JAK1/JAK2JAK1JAK2

    JAKSTAT1SH2STATSH2SH2

    STAT


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JAK-STAT


3 smad

3. Smad

  • TGF-SmadSmad

  • STATSmad

  • TGF-/

  • TGF-22Smad2Smad3Smad2Smad3Smad4Smad


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TGF


4 pi3k

4. PI3K

  • -3-PI3KPI-3K

  • PI3Kp85p110PI3KPIP3

  • PIP3BPKBPH

  • PKBc-aktAktPKB

  • PI3KPKB/AktPI3K-AktPI3K-PKB


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5. NF-B

TNF-R1NF-Bnuclear factor-BNF-B

NF-B


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NF-B


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The basic rule and complexity of signal transduction and


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The Abnormal of Cellular Signal Transduction and Disease


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