Download Signaling

Ligand
Receptor
Receptor/Ligand Binds to promoter elements in DNA and regulates transcription
Cortisol Receptor is located in the cytosol
Nucleus:
Retinoid Receptors are in the nucleus
Target gene in the nucleus
Promoter
Regulation of Transcription
Primary and Secondary Responses
Promoter
Promoter
Activation of transcription
Inhibition of transcription
K) There are three major classes of cell surface receptors
extracellular
space
M) Signaling via G protein linked receptors
adenylyl
receptor G protein cyclase
bg a
membrane
cytosol
GDP
ligand
GTP
ATP
cAMP
Pi
cAMP
Regulation of
Transcription
P
CREB
CRE
Some G protein linked receptors linked to Gq activate Ca2+ signaling
PIP2 plays an important role in Ca2+ signaling
PI
PIP2
Cleavage of PIP2 gives rise to Ca influx
Gq
PKC
(PLC b)
ER
Ca2+
Calcium channel
Calmodulin is a Ca2+ receptor that mediates many Calcium responses
CAM Kinases mediate most Ca2+ responses
CAM Kinase II
Interactions between cAMP and Ca pathways
cAMP phosphodiesterase and adenylyl cyclase
are regulated by CAM Kinases
PKA Ca channels
Some CAM Kinases are PKA targets
CAM Kinases and PKA common targets
Regulation of
Transcription
Regulation of
Phosphorylase
Kinase by cAMP
and Ca
P
CREB
CRE
e) phosphorylase kinase is regulated by cAMP and calcium
2) Receptor tyro sine kinase (RTK) family o f receptors
Ligand binding usually causes dimerization of the receptor
EGF EGF
outside of the cell
Membrane
P
P
P
P
inside of the cell
P-Tyr binds downstream regulators containing SH2 domains
SH2 Domain
PI3K
P
P
GRB2
GAP
P
P
PLC
Ras pathway
Ras superfamily of small GTPases help relay signals from RTKs
Stimulus
GEF
GDP
GTP
Inactive
Active
GAP
Downstream
Signaling
Pathways
d) drosophila eye development and RTK signaling
d) drosophila eye development and RTK signaling
Mammalian Ras activation
Drosophila Ras activation
SH2 Domain
PI3K
P
P
GRB2
GAP
P
P
PLC
(DRK)
SOS
Ras
GTP
Downstream
pathways
MAP Kinase Pathways can be mediated by
members of the Ras superfamily
Stimulus
Usually Ras superfamily
Yeast MAP Kinase pat hways
Mat ing/
Dif f erent iat ion
.
Cell Wall
Int e grit y
Osmot ic
St re ss
G bg Cdc4 2
STE 2 0
PKC1
STE 1 1
BCK1
SSK2 / 2 2
MAPKKK
STE 7
MKK1 / MKK2
PBS2
MAPKK
MPK1
HOG1
MA PK
S
T
E
5
SSK1
KSS/ Fus3
Ca2+ signaling can be activated by RTKs via PLC g
PI3K
P
P
GRB2
GAP
P
P
PLC
Ca2+ signaling
Cleavage of PIP2 gives rise to Ca influx
RTK
PLCg
ER
Ca2+
Calcium channel
RTKs can activate PI3-Kinase
Other signaling pathways
Cell survival
PI3K
P
P
GRB2
GAP
P
P
PLC
PI3 Kinase (PI3K)
PI(3)P
CH2
C
O
O
O
CH
OH-
O
CH2
O
P
CH2
C
PhosphatidylInositol(PI)
O
PI3K
CH2
C
CH2
O
4
3
OH
6
2
OH-
O
1
OH
O
CH2
O
P
5
4
3
OH
6
2
1
OH
CH2
C
CH2
C
O
O
CH
O
O
5
O
CH2
O
O
O
PI3K
+
PI4K
PI(3,4,5)P2
PI(3,4)P2
OH-
O
CH2
C
O
O
CH
CH2
O
P
CH2
C
CH2
O
O
OH-
O
5
3
OH
O
6
2
1
OH
CH2
O
P
4
5
6
3
OH
2
1
OH
Cell Survival Pathways
Other Signaling Pathways
CH2
C
O
CH
+PI5K
O
4
O
CH2
O
O
PI3 Kinase (PI3K) and cell survival pathways
PI(3)P
CH2
C
O
O
O
CH
OH-
O
CH2
O
P
CH2
C
PhosphatidylInositol(PI)
O
PI3K
CH2
C
CH2
O
4
3
OH
6
2
OH-
O
1
OH
O
CH2
O
P
5
4
3
OH
6
2
1
CH2
C
CH2
C
O
O
CH
O
O
5
O
CH2
O
O
O
PI3K
+
PI4K
PI(3,4,5)P2
PI(3,4)P2
OH-
O
CH2
C
O
O
CH
CH2
O
P
CH2
C
CH2
O
O
OH-
O
5
OH
3
OH
4
1
OH
PH
AKT
O
6
2
5
6
3
OH
2
1
OH
PH
P
SER
PDK1
ser
BAD
CH2
O
P
CH2
C
O
CH
+PI5K
O
4
O
CH2
O
O
PI3K - AKT - Cell Survival
AKT
P
SER
BAD
1 4 -3 -3
P
SER
BAD
BAD
Mit ochondria
BCL - 2
BCL- XL
BCL - 2
BCL- XL
cyt ochrome
is released
C
Caspase
Cacade
Mit ochondria
Inhibit ion of
Cyt ochrome C
r elease
Cell Deat h
Su r v iv al
Tyrosine Kinase (TK) Associated Receptors
LIGAND
outside of the cell
Membrane
P
P
P
P
inside of the cell
Src binds to receptors with and without Tyr Kinase activity
Schwartzberg (1998) 17; 1463
PI3K
P
P
GRB2
Src
P
P
PLC
Cell proliferation,
Gene expression, …
e) Janus family of non-receptor TK s also bind some receptors
receptors
i) growth hormone receptors
ii) prola ctin receptors
iii) some cytokine receptors
LIGAND
iv) include JAK1, JAK2, Tyk2
v) more poorly characterized
P
P
Q) Signal Transduction and the Cytoskeleton