Signal Transduction

Mechanism

RTK|GPCR|LigG|Nuclear/IC R

RTK

EGF|NGF|PDGF|CSF|FGF|VEGF
EC|L-binding|IC|Tyr kinase activity
2|transmem|Tyr kinase domain
2|hormone-binding site
2xL|full activation|phos IRS-1
SH2|Ras|Raf|Mek|Erk|Elk|c-Myc
PI3K|GLUT4|mem|Glc|Glg

Insulin R

CML

BM malignancy|Phili|9:22|Abl:Bcr
Abl-Bcr fusion|reg Tyr K|Gleevec
Gleevec|Abl-Bcr|Tyr K

B-raf

Ser/Thr K|reg MAP K pathway|+prolif

V600E|melanoma|PLX4032|Zelboraf

GPCR

CA|NT|pepH
2nd msgr|cAMP|DAG|PI3|Ca|cGMP
cAMP|PKA (R2C2)|Pl'ase||P'ase|PDE

S
1

Gq

PS
M1

Gq

D
D1

Gi

M2

Gi

D2

1
2

Gs
Gs

M3

Gq

1|1|V1|M1|M3

Gs

H
H1

Gi

H2

Gq

Vp
V1

Gq

Gs

V2

Gs

Gq|PLC|PIP2|DAG|PKC
IP3|Ca|Sm m
1|2|D1|H2|V2
Gs|AC|cAMP|PKA|Ca
M2|2|D2
Gi|AC|cAMP|PKA|MLCK
Ca-CaM
MLCK|NOS|
MLCK
Phos myosin|muscle contraction|
ACh sm m contraction
NOS
NO|relax vasc sm m|vasoD
ACh@vac endothelium
Adr
E|NE
Cholinergic
Ach
PDE5
corpora cavernosa
PDE3
heart
Viagra
affect PDE5 more

SERM (Selective Estrogen Receptor Modulator)

E-R Agonist
E-R Antg

U|Br|Bn
U|Br|Bn

Uterus
Breast
Bone

High Co|Low Co
Low Co|High Co
High Co|Low Co

U=endometrial CA
Br=breast CA
Bn=osteoporosis
***Some Rx can be agonist or antagonist depending on
the tissue they are in***
Different Rx effects depends on which Co-reg is
expressed more in the tissue. Some Rx have
preference for one or the other Co-reg (ie. Rolaxifen)
while others go with the flow and exhibit the effects
of the more expressed Co-reg (ie. Tamoxifen).
Faslodex (ICI) is a global antagonist meaning that it
always recruit Co regardless of the [] in the tissue
Estradiol (E2) is a global agonist meaning that it
always recruit Co regardless of the [] in the tissue
Tamoxifen has no preference for Co or Co; dep
solely on which Co-reg is higher
Raloxifen prefers Counless [] diff is too great to
ignore
Tamoxifen
Clomiphene
Raloxifene

Br|Anta|Bn|Antg|U|Agonist
HTh|Antg|Br|NOT Antg
Bn|Antg|U|Antg|Br|Antg

Orphan R

Nuclear|No known lig|reverse endocr

RXR|PPARa|PPARg|LXR|FXR

"Orphan" means NO known ligands

New approach to Rx discovery
Traditionally Rx are discovered going from physiology
Reverse endocrinology starts at the Gene level
GeneRHPhysiology
Insulin mediate Glc-Lipid crosstalk
Ins
Glc uptake|lipolysis|
DM-II
tissue|hypoGlc|blood|hyperGlc
PPAR
PPAR
PPAR
PPAR
TZD
LXR

burns fat|liver|muscle|FA|fibrate Rx
FA|ArachA|TZD|Ins sensitiation
up fat storage|mntn Ins sensitivity
ubiquitous expr|low amt|sim to

up Glc uptake|up lipid uptake|up E expndtr

Liver X R|chol sensor|meta tissues|
Chol metabolites|reg chol homeostasis

FXR
CAR
SXR

Farnesoid X R|Bile sensor|liver|intestine

Bile|reg bile efflux|solubilize lipid & vit
constitutive androstane R|phenobarbital
steroid X R|prscrp Rx|steroid|envrn tox
CYP gene|p450|CYP3A|detox & CL 60% Rx
MDR gene|metabolite export