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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



  • cell communication

  • signal transduction


The General Information of Signal Transduction


()

target cell

()

()


gap junction


  • chemical signaling



endocrine

paracrineautocrine

neurotransmitter




  • TB


  • receptor

  • ligand



19-1





-


  • signal transduction pathway


  • cross-talkingsignal transduction network


RNA

RNA

NH2

m7G

AAAAA

Translation


Intracellular Signal Molecules


  • signal transducer



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






  • cAMPcGMP


  • cAMPcGMP


1. cAMPcGMP

adenylate cyclaseAC

guanylate cyclaseGC


2.

  • phosphodiesterasePDE

  • cAMPPDEcAMPcAMP

  • PDEcAMPcGMP


3

  • cAMPcGMP


AcAMP

  • cAMPcAMPcAMP-dependent protein kinasecAPKAprotein kinase APKA

  • PKA


cAMP PKA


GcGMP

  • cGMPcGMPcGMP-dependent protein kinasecGPKGprotein kinase GPKG

  • PKGPKAPKGPKG


cGMPPKG


4cAMPcGMP

  • cAMPcGMP

  • cGMP-

  • -


  • 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

  • :


  • PI-3KPI-4KPI-5K

  • C PLC-4,5-PIP2DAGIP3


PLA1

PLD

PLA2

PLC

PLC

3

2

1

4

A

6

5

-1235--46-



2

  • DAG

  • IP3


IP3 IP3

IP3

  • IP3IP3


DAGC

  • Cprotein kinase CPKC/

  • PKC

  • PKC12


DACPKC

DAG

Ca2+

DAG

Ca2+


1

  • 1.12~1.23mmol/L

  • 90%Ca2+0.01~0.1mol/L


  • Ca2+

  • Ca2+Ca2+-ATP


2

  • calmodulinCaMCa2+

CaM

Ca2+

Ca2+

Ca2+

CaM

Ca2+

Ca2+


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).


  • CaMCa 2+/CaM-CaM-K

:

:

2:

CaM-K

Ca2+/CaM- I

CaM-K

Ca2+/CaM- II


3

  • Ca2+PKCACcAMP-PDE


+

NH2

H2N

NH

+

COO-

H2N

O

H2N

NH

+

COO-

H2N

NO

  • NONO

NO

NO


NO

.

GTP

cGMP

cGMP

  • NOADP-


  • NOcarbon monoxideCOsulfureted hydrogenH2S


    • CDPLD

    • /


/

  • protein kinaseprotein phosphatase


Thr

Ser

Tyr

Thr

Ser

Tyr

-OH

ATP

ADP

-O-PO32-

Pi

H2O


1. /

  • ATP -800


2.

  • (phosphatidase)


PTK

PTP

PTP

P

PTK

Src

family

PTK

Src family

PTK

P

P

S

S

PTK

PTP


  • /

  • /


/

  • /

    • PKAPKG

    • DAG/Ca2+PKC

    • Ca2+/CaMCa2+/CaM-PK

    • PIP3PKB

    • mitogen activated protein kinase, MAPK


1. MAPK

  • MAPK

  • extracellular regulated kinaseERK

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

  • p-38-MAPK


  • ERKERK

  • JNK/SAPK

  • p38-MAPK


2. MAPK

  • MAPKMAPKKMAP kinase kinaseMAPKKKMAP kinase kinase kinase

  • MAPKKMAPK

  • MAPKKKMAPKKKMAPKKMAPK


MAPK

MAPKKK

P

P

MAPKK

Thr

Tyr

Thr

Tyr

MAPK

MAPK

phosphatase

on

off


  • MAPK

  • MAPK

  • MAPK


RafMAPKKK

MEKMAPKK

ERKMAPK

ERKRaf-MEK-MAPK

  • ERKERK1ERK2ERK3

  • ERK


MEKKMAPKKK

JNKKMAPKK

JNK/SAPKMAPK

JNK/SAPK()

  • JNK/SAPK


apoptosis signal regulating kinase 1ASK1

MAPKKK

MKK3/MKK6MAPKK

P38-MAPK

P38-MAPK

  • P38-MAPK


  • Protein Tyrosine kinasePTK

  • TB


1. PTK

  • PTK

  • PTK

  • PTKSH2


PTK

PTK

HGFR

EGFR

IGFR


2. PTK

  • PTK

  • PTK


PTK


  • JAKjust another kinasejanus kinase

  • Src(Rous sarcom)


  • G


GGTP/GDP

  • guanine nucleotide binding proteinG proteinGGTP

  • GTPGDPG

  • GTP

  • GGTPGTPGDP


  • G

  • G7G(G)

  • G21kD


GG

GDP/GTP

GTP

G

(G)


  • GGG protein-coupled receptorsGPCRsPLC


2. G

  • G21kD

  • RasGRas

  • Ras50


Structure of Ras with GDP


  • G

  • guanine nucleotide exchange factorGEFguanine nucleotide release proteinGNRP

  • guanine nucleotide dissociation inhibitorGDIGTPGAP


1.

  • signaling complex

  • protein interaction domain



SH2

PH

SH3

Btk

TH

SH2

SH3

SH3

Grb2

stat

SH2

DNA

TA

PTB

SH2

tensin

//


Pleckstrin Cplatelet and leukocyte C kinase substratekstrKSTR


SH2


SH3


PH(pleckstrin homology domain)

  • G ,


2.

  • adaptor protein

  • 22


2014112731


3.

  • scaffolding proteins


Signal Pathways Mediated by Different Receptors


G-



  • DNA

  • D


  • -

  • Hsp90DNA-

  • -

  • -




  • -ligand-gated receptor channel





  • -


Ion-channel linked receptors in neurotransmission


GG

  • GGPCRGG

  • GGPCR


  • GPCRserpentine receptor


Alfred G. Gilman

Martin Rodbell

  • G1994


G

+

G


G


  • GACPLCeffector

  • ACGss stimulateiiinhibit


G


G


1. cAMP-PKA

  • cAMPPKA

  • PKA/


1. cAMP-PKA


1


Glycogen breakdown in skeletal muscle



2


3

  • PKA


2. IP3/DAG-PKC

GPLC

PLCPIP2DAGIP3

IP3Ca2+Ca2+

Ca2+PKCDAGCa2+PKCPKC


2. IP3/DAG-PKC

  • PKC

  • PKC

  • PKC


Phorbil ester()

AP1Fosc-jun

PKC


3. Ca2+/

  • GCa2+

    • G

    • PKACa2+

    • IP3Ca2+



  • Ca2+

  • Ca2+/CaMCa2+/CaM

  • / MLCKPhKCal-PK


  • 1



  • -

  • -


  • MAPK

  • JAK-STAT

  • Smad

  • PI3K

  • NF-B


1. MAPK

  • MAPKMAPKMAPK

  • MAPK12ERKp38 MAPKJNK


Ras/MAPK

  • epidermal growth factor receptor, EGFRPTK

  • Ras/MAPKEGFR



EGFR


2. JAK-STAT

  • JAKJanus kinase

  • JAKsignal transducer and activator of transcriptionSTATJAK-STAT


  • JAK

  • JAKJAKSTAT

  • STATSTAT

  • JAKSTATJAKSTAT


  • IFN-JAK1/JAK2-STAT1

    IFN-

    JAK1/JAK2JAK1JAK2

    JAKSTAT1SH2STATSH2SH2

    STAT


JAK-STAT


3. Smad

  • TGF-SmadSmad

  • STATSmad

  • TGF-/

  • TGF-22Smad2Smad3Smad2Smad3Smad4Smad


TGF


4. PI3K

  • -3-PI3KPI-3K

  • PI3Kp85p110PI3KPIP3

  • PIP3BPKBPH

  • PKBc-aktAktPKB

  • PI3KPKB/AktPI3K-AktPI3K-PKB


5. NF-B

TNF-R1NF-Bnuclear factor-BNF-B

NF-B


NF-B


The basic rule and complexity of signal transduction and




The Abnormal of Cellular Signal Transduction and Disease













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