Co

ur
sR
SI
C
M1
Réseaux signalétiques et
S P
incidences cellulaires
BS
RSIC 20
M1SP 22
/20
23
 Co
ur
s R Cell signaling
SI
C
M1
S
Mechanism by which stimuli are transmitted via a cascade to
P the appropriate response by
effector molecules that orchestrate
reprogramming various biochemical, BS genetic, and structural
processes
20
22
/20
Cellular communication and environmental adaptation
23
 Co Forms of Cell signaling
ur
sR
SI
C
M1
SP
BS
20 Direct

Endocrine 22
Synaptic

/20
23
 Co
ur
s Rof cell signaling pathways
Types
SI
C
M
Checkpoint signaling 1 Stress signaling
SP
Lipid signaling Morphogen signaling
Growth factor signaling
B SHippo signaling
Nutrient signaling
2
TOR02signaling
Insulin signaling
2 /20
Integrin signaling
23
Signaling networks and cellular incidence
Co
ur Cell signaling controls various
sR cell functions

SI
C
M1 Key biological processes such
as cell division, differentiation,
SP growth, and cell-cycle transition

BS specialized cell-specific
functions such as

20 neurotransmission, pathogen-
sensing, phagocytosis,

22
antigen-presentation.
autophagy
/20
and nutrient cycling and
recycling.
23
 Co
ur
s R Cell Signaling
SI
C
Mtheir
Signaling molecules and 1S receptors HORMONES
RCPG and G protein P
B S EGF PI3K/TOR
Growth factor signaling and their receptors
Insulin signaling 20
2
Receptors Coupled to Transcription Factors 2 /20
TGF
23
 Co
ur
sR
Components of Cell Signaling
SI
C
M1
How the messages are relayed from the membrane to the nucleus where gene expression,
subsequent translations, and protein targeting to the cell membrane and other organelles
are triggered. SP
BS
The messages are transferred from the first messenger (ligand) to the receptor, and then
decoded with the help of cascades of second messengers (kinases, phosphatases,

20
GTPases, ions, and small molecules such as cAMP, cGMP, diacylglycerol….).
Reception, transduction, response Signaling phases
22
Although there are limited numbers of intracellular messengers, the specificity of the
/20
response profiles to the ligands is generated by the involvement of a combination of
selected intracellular signaling intermediates.
23
Co
ur
sR
SI
C
M1
SP
BS
20
22
/20
23
 Co
ur
s Signaling
RS molecules
IC
M1
Signals are perturbations of cellular homeostasis , there are different stimuli such as growth
factors, hormones, cytokines, neurotransmitters, extracellular matrix components, etc.

Mechanical
SP
Electrical
BS
Chemical, the majority of the signals are chemical in nature
20
Chemical ligands is diverse including small molecules such as
22
lipids (prostaglandins, steroids),
/20
proteins (peptide hormones, cytokines, and chemokines, growth factors),
complex polymers of sugars (glucan and zymosan),
and their combinations (e.g., proteoglycans),
23
nucleic acids…...
 Co
ur
Soluble lipophilic ligands

sR
ligands (small molecules, peptides, and proteins) are polar or
sometimes too large and cannot pass through the plasma
membrane
SI
Most of these ligands bind to the extracellular domain of cell-
surface receptors. C
M1
SP
Small hydrophobic ligands can directly diffuse through the
plasma membrane and interact with internal receptors
(steroid hormones, thyroid hormones and vitamin D).
BS
20
Steroid hormones have similar chemical structures to their
precursor, cholesterol. 22
/20
23
 Co
Others small ligands (neurotransmitters such as acetylcholine and
γaminobutyric acid, and plant hormones such as auxins)
ur
sR
NO, due to its small size, diffuses across the plasma membrane and activates pathways
regulating vasodilation.
SI
C
But many neurotransmitters are small hydrophilic molecules that bind to ion
channels on adjacent cells.
M1
SP
BS
20
22
/20
23
 Co Nitric Oxide Signaling
ur
sR
Nitric oxide (NO) is a gas that can diffuse

SI
directly across the plasma membrane.

C
Due to this property, NO, like steroid
M1
hormones, can bind to an intracellular
receptor.
SP
NO plays an important role regulating blood

BS
flow by relaxing smooth muscles around
blood vessels (resulting in an increase blood
flow).
20
In response to neuronal signaling, NO is
released from endothelial cells and binds to 22
its intracellular receptor, guanylyl cyclase
(GC), in adjacent smooth muscle cells.
/20
23
CNitric
ou
Oxide Signaling

rs
RS Guanylyl Cyclase (GC) is an intracellular

IC receptor for nitric oxide (NO) and an

enzyme.
M1
SP When NO is bound to GC, GC convert
guanosine triphosphate (GTP) into cyclic
BS
guanosine monophosphate (cGMP).

20
22
cGMP is a necessary secondary messenger
/20
in the NO signaling pathway.
cGMP can be broken down into guanosine
23
monophosphate (GMP) by enzymes called
phosphodiesterases (PDE).
 Co
Nitric Oxide Signaling

ur
sR In response to neuronal signaling, endothelial cells that wrap
around blood vessels produce the small gas Nitric Oxide (NO).
SI
C NO diffuses out of the endothelial cells and into adjacent smooth
muscle cells. Inside the smooth muscle cells, NO binds to its
M1
intracellular receptor, guanylyl cyclase (GC). When active, GC
metabolizes GTP into the secondary messenger cGMP.
SP
Increasing levels of cGMP led to the activation of effector

BS
proteins, such as myosin light chain kinase, which led to
muscle relaxation. As the smoothing muscles around the blood
vessels relax, blood flow increases.
20
22
The drug Viagra targets phosphodiesters (PDE), enzymes that
break down cGMP into GMP. By inhibiting the breakdown of the
/20
secondary messenger cGMP, Viagra maintains high cellular
levels of cGMP, thus maintaining smooth muscle relaxation,
increased blood flow.
23
 Co
ur
s Signaling
RS Receptors

2 categories of receptors C
I
M1
cell-surface receptors and intracellularSPreceptors.
Cell-surface receptors are involved in mostB
S
of the signaling in multicellular
organisms.
20
3 categories of cell-surface receptors: 22
/ 20
ion channel receptors
G-protein-linked receptors 23
enzyme-linked receptors.
 Co
ur
sIntracellular
RS receptors
IC
M1
Nuclear receptors (for e.g., androgen receptor, estrogen receptor, glucocorticoid

SP
receptor, progesterone receptor, retinoic acid receptor thyroid receptor, etc.)
hormones, metabolites, or enzymatic ligands, as well as unidentified ligands

BS
Cytoplasmic receptors, or organellar receptors like in mitochondria, endoplasmic reticulum,
and Golgi apparatus (subcellular compartments) that bind to small lipophilic molecules,
which cross the plasma membrane. 20
2 2/2
For example, receptors for glutamate, thyroid hormone, estrogen, and androgens are also
present on the mitochondrial membrane.
02
3
Sigma receptors are found to be associated with the endoplasmic reticulum membrane
and act as a chaperone to stabilize ER membrane proteins like IP3 receptor.
Co
ur
sR
SI
C
M1
SP
BS
20
22
/20
23
 Co
ur
sNuclear
RS receptors NR
IC
The NR superfamily over 500 members.
M1
divided into 4 classes based on dimerization, DNA binding motifs and specificity, and ligand
binding.
SP
Steroid Receptors (Class I) also known as nuclear hormone receptors
BS
RXR heterodimers (Retinoid X receptor, Class II)
Homodimeric orphan receptors (Class III)
20
Monomeric orphan receptors (Class IV)

2 2/2
NRs involved in key physiological functions such as cell growth and differentiation,
development homeostasis, or metabolism
02
Inappropriate exposure to environmental pollutants, which have the ability to substitute for
3
natural ligands, can cause proliferative, reproductive, and metabolic disorders : hormone-
dependent cancers, infertility, diabetes, or obesity.
 Type I nuclear receptors bind to HREs consisting of two
Co half-sites separated by a variable length of DNA, and the

ur second half-site has a sequence inverted from the first

(inverted repeat).
sR
Dimerization
SI
(homo, hetero, or mono)
C
M1
DNA binding
(direct repeat or inverted SP
Direct Repeat Inverted Repeat

repeat)
BS
20
ligand specificity
(required, or not required) 22
/20
23
 Co
ur
En résumé
sR
SI
Les récepteurs nucléaires constituent une superfamille dans laquelle on

C
retrouve 4 grandes classes de récepteurs.

- M1
Les récepteurs des stéroïdes formés de dimères de glucocorticoïdes, de
progestérone, d’œstrogènes
SP
- Les RXR, rétinoïdes récepteurs qui sont des hétérodimères puisqu’ils vont
BS
associer un RXR avec un RAR (acide rétinoïque), un VDR (récepteur à la
vitamine D) ou avec un thyroid hormone receptor.
20
- Les dimeric orphan receptor qui associent deux RXR
22
/20
- Les monomeric orphan receptor qui fonctionnent de façon monomérique

23
 Co
ur
N-terminal domain DNA-binding domain Variable C-terminus

sR Hinge region Ligand-binding domain

SI
All NR contain a
C
variable N-terminal domain (NTD), a DNA
binding domain (DBD),
a hinge region,
M1
SP
a conserved ligand-binding domain (LBD),
a variable C-terminal domain.
BS
The 2 most highly conserved domains amongst all NR are DBD and LBD
20
The DBD contains 2 zinc finger motifs, which act as a hook, that allow binding to
chromatin within the nucleus.
22
/20
Each class has different DNA binding recognition sequences, which range from variable
half-sites with inverted repeats, direct repeats, or no repeats within the DNA sequence
23
 Co Fixation de
l’Hormone
ur
sR NLS

SI
C
M1 Permet le

Facteur SP
changement
de
conformation
régulateur
du R et la
dimérisation BS
Domaine doigt de zinc 20
domaine (le + conservé) de 22
fixation à l’ADN sur HRE,
hormone responsive element /20
23
The AF1 and AF2 activation function 1 and 2 contact co-regulatory molecules, but AF-1 is typically a variable
ligand-independent (first named transactivation domain. TD) while the AF-2 of the E/F region is ligand-
dependent.
 Co
NR functional domain organization and most relevant regulatory functions

ur
sR
SI
C
M1
SP
BS
All NR domains undergo post- translational modifications (PTMs), which could regulate protein

20
stability , and multiple domains are involved in interactions with co- regulator proteins (protein–
protein interactions (PPI)).

22
As well as proteins that operate in the nucleus, NRs harbour a nuclear localization signal (NLS).
/20
23
 Co
ur
The LBD of NR remains highly conserved

sR
in function but differs in specificity and
affinity to specific ligands.

SI
All classes, excluding orphan receptors,
are ligand-activated. C
Ligand binding at the LBD induces an
M1
allosteric change, inducing activation.
Ligands within each class of nuclear
SP
receptors have similar structures.
BS
Classes I–III require dimerization within
the nucleus while Class IV does not.
20
22
Class I and III require
homodimerization provide stronger zinc
/20
finger binding to DNA
Class II requires heterodimerization.
23
 Co
ur
sR
SI
Class I
C
M1
SP
Class II BS
20
22
/20
23
 Co
ur
sR
SI
Class I
C
M1
SP
BS
20
22
/20
23
 Co
Schematic model of NR function Class I vs Class II

ur
sR Type III receptors reside in
SI the nucleus and exchange

C bound co-repressors and

M1 co-activators. These
receptors bind to

SP direct repeat HREs as

homodimers.

BS Type IV receptors are

almost identical to Type III

20 except they bind HREs that

are extended
22 half sites as monomers.

/20
Before ligand binding, type I NRs form inactive complexes with chaperone proteins in the cytoplasm

23
(AR) or in the nucleus (ERs) whereas type II NRs (RXR heterodimers) are bound to their target genes
with corepressors. Ligand binding results in the dissociation of chaperone proteins and binding and
activation to target genes for type I NRs. Ligand binding results in corepressors release and
coactivator recruitment for type II NRs
 Co Shematic NR regulation

ur
sR
SI
C
M1
SP
BS
( A) To activate gene expression, NRs (blue) interact with their
DNA response elements. DNA-bound NRs recruit co-activator 20
(B) To repress transcription, NRs recruit co-repressor
proteins (orange). These proteins recruit other histone
proteins (magenta), which in turn recruit histone-modifying
enzymes. These histone-modifying enzymes are commonly 22
deacetylases (red) that reverse histone acetylation and
restrict chromatin accessibility.
histone acetylases (green), which acetylate histone tails.
/20
This condensation prevents the transcriptional machinery
This modification is a mark of active chromatin. Ultimately, the
general transcriptional machinery and RNA Polymerase Pol II
(gray) are recruited to drive gene expression.
expression. 23
from accessing the DNA, thus repressing gene
 Co
Class I
ur
sR
SI
C
M1
SP
BS
20
22
/20
23
Class II
Co
ur
sR
SI
C
M1
SP
BS
20
22
/20
23
 Co
Histone acetyletransferase (HAT) and histone deacetylase (HDAC) families.
Chromatin conformation according to the HAT/HDAC balance. The acetylation levels of nucleosome histone tails, at
ur
lysine residues, are determined through the interplay between acetylation and deacetylation mechanisms engaged
sR
respectively through HATs and HDACs enzymes.

SI
C
The different families and classes of enzymes are noted.
Ac = Acetyl;
M1
CBP = cyclic adenomonophosphate response element-binding
(CREB) binding protein;
GNAT = Gcn5-related N-acetyltransferases; h SP
GCN5 =human general control of amino acid synthesis protein 5-
like 2;
PCAF = p300/CBP-associated factor;
BS
ELP3 = elongation protein 3;
MYST = MOZ/YBF2/SAS2/TIP60; 20
TIP60 = TAT interacting proteins 60;
22
TFIIIC90 = transcription factor IIIC 90kDa;
TAF1 = TATA Box Binding Protein-Associated Factor, /20
SRC1 = steroid receptor coactivator 1;
ACTR = SRC-3, steroid receptor coactivator/AIB-1, 23
 Co Therapeutic target
ur
sR
SI
C
M1
SP
BS
20
22
/20
Schematic mechanism of histone acetylation and deacetylation enzymatic control and
inhibitors. HAT, histone acetyl transferase; HDAC, histone deacetyl
transferase; HDACi, HDAC inhibitors
23
 Co
Histone acetyltransferase (HAT) activation as a therapeutic strategy

ur
sR
SI
C
M1
SP
BS
Ac=Acetyl;
NFκB=nuclear factor kappa B; 20
UBF-1=upstream binding factor-1;
CoAct=coactivator; 22
CoRep=co-repressor;
TF=transcription factor; /20
RNApolII=RNA polymerase
23
 Co NR Signaling

ur
sR
SI
C
M1
SP
BS
20
(B) In a canonical signal-transduction cascade, receptor binding at the plasma membrane initiates enzymatic phosphorylation
cascades culminating with transcription factor translocation into the nucleus.
22
/20
(C) Type I steroid nuclear receptors are synthesized in inactive forms associated with heat-shock protein (HSP) complexes in the
cytoplasm. Direct hormone binding causes a conformational change, dissociation from HSP complexes and translocation into the
nucleus.

23
(D) Type II heterodimeric nuclear receptors bind constitutively to DNA with RXRs as obligate partners. Ligand binding causes a
conformational change, dissociation of co-repressor complexes and recruitment of co-activators, such as PGC1a.
 Co ESTROGEN RECEPTOR ER

ur
sR
SI
C
M1
SP
BS
The percentage of homology between the different domains

20
The number of amino acids for each receptor
22
/20
Estradiol (E2) mediates numerous phenotypic effects in cells by binding to and activating ERs

23
Genomic
Co ER mechanism of action

ur
E2 enters the cell through the lipid membranes

sR
and binds ER, which can be present in the
cytoplasm and the nucleus.

SI
The activated ER forms a dimer to tightly fix
C
chromatin directly at the estrogen-responsive

M1
element (ERE) sites or indirectly at activator
protein 1 (AP1) or specificity protein 1 (Sp1)
sites.

ER is then able to remodel chromatin by

SP
recruiting cofactors and activating RNA
polymerase II (Pol II), at target genes (genomic
BS
action).
20
Non Genomic 22
Besides, ERs can use rapid non-genomic
action through the interaction with intracellular /20
kinases (mitogen-activated protein kinase
(MAPK), phosphatidylinositol 3-kinase (PI3K), .
. . ) and the growth factor (GF) receptor GFR)
23
pathways.
 Co
ur
sR
SI
C
M1
SP
ER Signaling
BS
20
22
/20
23
 Co
GPER G-coupled estrogen receptor, E

ur
estrogen, MAPK mitogen-activated protein kinase, PI3K
phosphatidylinositide

sR
3-kinase, PKA protein kinase A, AKT protein kinase B,
EGFR epidermal growth factor receptor, CREB cAMP response element
binding protein, CTGF connective growth tissue factor, EGR1

SI
early growth response 1, TF transcription factor.

C
M1
SP
ER Signaling
BS
20
22
/20
23
 C ou
Estrogen metabolites
rs
and carcinogensis
RS
I
Simplified diagram demonstrated the effect of
estrogen metabolites produced by CYP1B1 in cells
C
including structures (grey field) and processes
(cyan field). Blue arrows indicate the direction of
the reaction. EM estrogen metabolites, ER
M1
estrogen receptor, ROS reactive
oxygen species, CYP1B1 cytochrome P450 1B1. SP
BS
20
22
/20
23
 Co The Anti-Cancer Charm of Flavonoids: A Cup-of-Tea Will Do!

ur
sR
Various flavonoids and
phytoestrogens either
antagonize estrogen
SI
synthesis, mimic estrogen
activity by binding to the C
estrogen receptor and
activating it or by binding to
M1
the ER and preventing ER
activation.
SP
Genistein, daidzein, equol, BS
miroestrol, deoxymiroestrol, 8-
phenylnaringenin, coumestrol 20
and resveratrol do not
necessarily inhibit nuclear 22
transport of dimerized
estrogen receptors, but they
/20
do prevent the activation of
estrogen-dependent
23
transcription.
Co
ur
sR
ER could also be activated via phosphorylation by
growth factor receptor and downstream signaling
activation or mutations in its ligand-binding domain,

SI leading to estrogen-independent target gene

regulation. In addition, membrane-bound ER

C crosstalks with growth factor receptor signaling that

promotes estrogen-independent tumor growth. Cyclin

M1 D is a central transcription target of ER and growth

factor receptor signaling pathways, which activates
CDK4/6 and induces cell cycle progression from G1 to

SP S phase. Cyclin D/CDK4/6 activation is often

associated with endocrine resistance. Classes of
drugs in the clinic or in development that inhibit

BS estrogen production, ER function, or degradation, and

inhibitors against PI3K, mTOR, or receptor tyrosine
kinases are highlighted

20
22
/20
23
 Co Typical heterodimer

ur
sR
SI
C
M1
SP Typical heterodimers are defined here as the well-
characterized heterodimers of which both partners
contact DNA , sharing RXR as a common protein partner.
BS
Examples include pairings with (isoforms of)
Typical NR dimer binding to DNA takes place
at cognate DNA response elements featuring 20
liver X receptor (LXR),
peroxisome proliferator activated receptor (PPAR),
(imperfect) palindromic sequences or two
22
pregnane X receptor (PXR),
hexanucleotide half- sites organized as direct,
everted or inverted repeats. /20
retinoic acid receptor (RAR),
retinoid X receptor (RXR),
thyroid receptor (TR),
vitamin D receptor (VDR) 23
and some orphan receptors. BF3, binding function 3
 Co
RAR urs
R
The retinoic acid receptors
factors that belong toS
(RARs) are ligand dependent transcription

superfamily IC
the NR1B subtype of the nuclear receptor (NRs)

M1
S
Roles in development, cell growth and survival, vision, spermatogenesis,
inflammation, and neural patterning. P
B S with retinoid X
These receptors act in trans mainly as heterodimers
receptors (RXRs). 20
2 2/2 natural
The actions of RARs are stimulated by the binding of cognate
02
ligands (all trans retinoic acid) as well as a number of synthetic ligands.

3 Retinoic Acid Receptors (RARA, RARB, and RARC), 3