cellular signal transduction and dissease

1
cellular signal transduction anddissease
?????????
????
1??????? 2????????????????? 3????????????
2
???????????(concept)
??? ??????
cellular signal transduction
?????????????????????????,????????????????
?????????
??????????????????????
????????????? (composing)
1???(??) 2?????????????????? 3??????? 4????
3
??????
1???(ligand) ?????????????????,???
?? ????????????????????????,? ???????????????
2???(receptor) ?????????,????????,
????? ???????????????????????
4
????????????????
(?)?????????
???
??
??
???????? (????)
?
?? ?
??
???
cascade
?????????
5
G-protien-coupled receptor,GPC Receotor
tyrosinekinase,RTK ????????? ?/????????????
??????(TNFR,Fas) ??????????????
???
?????????
????????
????
???
6
(?)??????????????
G?????
7
G??????
??????????????7????,??7??????
8
G????? (Classification)
???????????????????????,?a?ß????????????,???????
??
??, ? 150??


??Ga???21?,???G ????? ????,
ß???5?,????11??
9
?????G????,????????
?Ras, Ras????????????????????????????????
???????RasGa?GDP????GTP???????,Ras?????,??????????
???????????????(mitogen activated protein
kinase, MAPK)????????????,?????????????????
10
? G????GTP?Ga???? G????GTP???GTP
11
G???????
12
1?Gs ?AC??cAMP-PKA
L??????????????

PKA ??????
(??)
(??????)
?????????????
PKA?
cAMP???????????????????
(??)
cAMP??????????????
 
2?Gi ?AC??cAMP?
13
Adenylyl cyclase signal transduction pathway
14
3?G??-???????
???A2???????
GPCR
???D????????
4?Gq?PLCß?
??????????
DAG??PKC??
(????? )
???????????????????????????
PLCß

IP3??????????/???? IP????
???,Ca2????????????
15
??? ???
Phospholipase C signal transduction pathway
16
5???MAPK?????????
????, ???,GPCR
??,??????, ????,GPCR
??
MAPKKK
Raf,Mos,Tp12
MLK3,TAK DLK
MEKK1,4, MLK3,ASK1
MAPKK
MEK1/2
MKK3/6
MKK4/7
MAPK
ERK1/2
p38MAPKaß?
JNK1,2,3/SAPK
????
????????
?????????????
17
G protein coupled receptor(GPCR)can activate MAPK
18
6?PI-3K-PKB??
?????-3?? (phosphatidylinositol
3-kinase)????PDK?????PKB(????B),??????????????????
???????????
7???????
GPCR?????????????????,?????????????????
?????????????????????????????????????????,
???????????????????
19
(?)????????????
???(nuclear receptor)???????,? ??????????????
??????????? ????????????????????????
?.???????????????????????? ??????????,????????
????? (heat shock protein, HSP)????,????????
?.???????? ????????D??????
??????????,??HSP??,??????? ???,???????????
20
??? ???????????
???????????????
1????????????????????????,???????????????
??????
2???G????G ???????GTP?GDP??,??GTP????????
a?ß?????????,???G ???????????????????????????????
????
21
3??????????
?????????????????????????????????????????

????
1????????
???????????????
???????????????,????????????????
Up - regulation
??????
Down - regulation
???????????????ß2????????
??????
22
???????/?????
?????????????????
????????????????????????????????????????
??
Gs
GRK
PKA
Gs
P
ß????
?????
??
P
P
?pH
ß????
???
??
ß2?????????????????
23
2????????
????????
?????-????????????????????????
???????????????????????????????????,??????????
????????????????????????????G-????????(G-protein-
coupled receptor kinases GRKs),?????GPCR???.??????
??????PKA?PKC,?????????????PKA?PKC???????,?PKC???
?????(EGF)???654?????????????????????
24
?????????
??????????????????????????????????????????
???????
?????????????????????GABAA???GABA???????,
?a?ß???d??5?????????????GABA??,???????????????????
??????GABAA???????GABA??????????GABA?????????
25
???????????
???????????????????????????????
??????????????(?PKA?PKC?MAPK?????)??????????????(?
???????????????????????)??????????,????????????,??
?????????????????????????????
???????????????????????????????????
26
??? ??????????????
????
(?)??????
1???????????????
?????????Toll???(Toll like receptor ,TLR)
?????????????,??????IL-1????,????????????????????
?????????
27
2?????????????
??????????Gsa??????201???Gsa?GTP???????????GTP
???GDP?Gsa?????????? ?AC? ? cAMP?(?100?)??????????
???? ??????????????? ??????,?????????
(?)?????
1???????????????-??????????G??K-Ras??12?13?
????,?Ras?GTP?????Ras???GTP?????????,? Ras
Raf(??MAPK kinase kinase ,MAPKKK)- MEK(??MAPK
kinase,MAPKK) - ERK (extracellular-signal
regulated kinase??????????)?? ????????
28
2??????
?????????????????????????????????????????
???????????????????????,?????????????????????????
???????PKC?ERK(extracellular-signal regulated
kinase )??
(?)?????
?????????????????,??????????,??????????????????
??????????????????,??????
1???????????? ?????? ??????????????????
29
2???????????
??????? ??????????????????(??????????(RT
K))???????????????????????????????????????(TSHR)?
?????????????TSH????TSH????????????
?????????
?????????????????????????,??????????(constitut
ively activated mutation)????????????????????????
TSHR??????,??????????
30
(?)??????
1? ????????????
?????????????????????????????????,???????????
?????????????????????????(Graves?,?????)??????????
??(??)???,??????????
2?????????
??????? ???????
31
(?)??????
?????????????????????,??????????????????????
?????????,??????????????????????????
?????????????
?????????????????????????????????????????
??????????????,??????????
32
??? ???????????
??????????????
??????????????????????? ????,?????????????
??????? ??????,??????????????????
??????????????????????? ??????,?????????????,????
????????????????,???????? ????,?????
33
Leprechaunism ??? Rabson-Mendenhall ??? A???????
? ?????????
?????(insulin receptor,
IR)?????????????????50????????????????insulin?IR??
???????????????(protein tyrosine
kinase,TPK)??,???????????(IRS)??PI-3K?Ras-Raf-MEK-
EGK?????????????
34
1??????????4???????????
????????
2??????????????
3???????,??????,????????
????????????????????,????????????,??????,?????
???,????????,??????????,???????????PTK???,?????,??
???????????????????????,???????????,????,????????
35
????????????????
????????????? ????????????????????????
????????????????
???????????????,?????????
?????????????Gsa???????GHRH??????GH????????
30-40????????Gsa???????????????Gsa????20
1????????????,????227???????????,???????GTP???,?Gs
a????????,AC????,cAMP????,??????????GH?????
36
????????????????
????????????,???????????????????????
???????????????????????????????????????????????
?????????????????????,???????????????,RNA????????,
?????????????????????????????????????,??????????(r
emodeling),??????????????????????????
37
??????????????????????????
????? ???????????????????????????,?????
???,?????????????????,??????????? ?????
?????????,??GPCR,?????????????????
??????? ?????????????????????????????TGFß?FGF????
???? ?????????????????
38
????
????
??????
??PLC-PKC
??MAPK??
??Na?Ca2??
PLCß
ERK?JNK?p38
?
Na/H????
IP3
DAG
?
????????? /????????
?? ?? ??
??? ??? ?? ??
PKC
?
????? ?????
??Ca-???? ???????
39
? ERK cascade is one of the important pathway.
Growth factor
Receptor TPK
40
???????????????
?? ????? ??????
??????
?????
????????? LDL??
??LDL??,?????? ???????? AnH V2???
????,???????? ?????????IL? 2??Y? T
???????,????
41
?? ????? ??????
?????

????????? ß?????? ???????,

???? ????????
????? ????,???
?????????? ??????? ???,???,
???????
???D?????? ???D?? ???????,??,
??????????
42
?? ????? ??????
???????? ????? ACh??
?????? ?????????
???TSH?? ????????
??? TSH??
??????? ?????
????? ???,?????

????? ????
ACTH??
????,??,???
43
?? ????? ??????
???????
???? ???????
??????? ???? ?????
?????????? ??
????? ???? ??
??????
??????
44
???
?20?????????????????????????,?????????????
??????????????????,???????????????,???????????????
??????????????????????????????????????????????????