Download How cells communicate with each other

Why communication is
important – introduction into
the world of cell signaling
Natalia Trempolec
A.R.Nebreda laboratory
Crazy about biomedicine,
01.06.2013
Outline
1. Human body complexity
2. Homeostasis
3. How do cell communicate – cell signaling
4. Cancer initiation and metastasis p38 MAPK – an
important negotiator
5. Synthetic lethality – how to get read of cancer
without killing the patient
Complexity of the human body
Cells
Tissues
Organs
Human body
How it is possible from 1 CELL obtain human
body made of trillions of different cells?
1. Cell proliferation
2. Cell differentiation
Cell signaling – or how do cell mantain
homeostasis
Homeostasis is the ability for the body to regulate its inner environment to ensure stability no matter what is
happening in the outside environment
Homeostasis controls:
-blood pressure
-body temperature
-respiration rate
-blood glucose levels which are maintained within a range of normal value
HOMEOSTASIS
Uncontrolled
Controlled
Positive
feedback
loop
body senses a change and
activates mechanisms that
accelerates that change
Negative
feedback
loop
deviation from a set point
causes a response that moves
the system back to the set
point
Disease
Metabolic
changes
cancer
How cells communicate with each other – introduction into
cell signaling
Reception
Cellular
response
Transduction
First messanger
(ligand)
+
Receptor
Second
messanger:
-cAMP or cGMP
- DAG
-
Ca2+
Protein
modification
Changes of
enzymatic
activity
How cells communicate with each other – introduction into
cell signaling
1. Endocrine signaling
- Signaling molecule
hormone
- Long distance
blood vessels
Hormones regulate:
System involved:
- nervous - information
- endocrine cell – release of hormons
- metabolism
- bloodstream - transport
- growth and development
- target cell
- tissue function
- sleep
- mood
How cells communicate with each other – introduction into
cell signaling
Example of endocrine signaling
Other factors
How cells communicate with each other – introduction into
cell signaling
2. Paracrine signaling
- Signaling molecule
protein, peptide, non organic ions
- Short distance
extracellular enviroment, local action
Signaling can regulate:
- cell proliferation
- cell death or survival
- migration
-Differentiation
-Metabolism
-other
Important facts:
- Specific - each of the signaling
molecule has to be percepted by
apopriate receptor
- Not cell type specific - one type of
the cell can affect (by secreatin
paracrine molecules) another type of
the cell
How cells communicate with each other – introduction into
cell signaling
Example of paracrine signaling
How cells communicate with each other – introduction into
cell signaling
3. Autocrine signaling
Examples of autocrine signaling:
- Signaling molecule
protein (also hormone), peptide
- Short distance
extracellular enviroment
- Self stimulation - immune cells produce factors which
after secretion, are recieved by the same cell – and leads
to amplification of the signal
-Positive feedback loop – cancer cells in order to
proliferate and avoid apoptosis produce survival and
proliferation factors which positively affect cell viability
How cells communicate with each other – introduction into
cell signaling
Example of autocrine signaling
How cells communicate with each other – introduction into
cell signaling
4. Juxtacrine signaling
- Signaling molecule
protein, sugar,
lipid, inside the
membrane
- Close contactmembrane
nanotubes,
„bridges”
Important facts:
- Cell-to-cell contract is required
- Is important during development and
generation of large compact structures
Why it is important to mantain an equilibrium?
Normal cell division
Cell damage
DNA damage
without repair
Cell commits suicide
Cancer cell division
Cell damage
DNA damage
without repair
More DNA damage
without repair
Uncontrolled cell
division
When everything goes wrong cancer initiation and metastasis
Cancer
Cancer cells invade tumor
border
Intravasion of blood
system
Cancer migration
Micrometastasis
Arrest extravasion
Progressive metastasis
and angiogenesis
Signal transduction - cascade of
phosphorylation events
Phosphorylation cascade is a sequence of events where one enzyme
phosphorylates another, causing a chain reaction leading to the phosphorylation
of thousands of proteins.
Kinase - type of enzyme that transfers phosphate groups from high-energy donor
molecules, such as ATP to specific substrates
All those events lead to signal
transduction. As a consequence –
binding of ONE messanger
molecule to the receptor can cause
multiple cellular changes
And everything starts with the proteins
Sumoylation
Phosphorylation
Ubiquitination
p38 MAPK is a key player in information delivery
and homeostasis
p38 MAPK
Family of protein kinases
Plays an important role in the cascades of cellular
responses evoked by extracellular stimuli such as osmotic
stress, UV, other secreated factors
Consists of four isoforms – p38α, p38β, p38γ and p38δ
Signal transduction is based on posttranslational
modification of target protein via phosphorylation
After phosphosphorylation protein changes its
conformation which leads to its activation
Inhibition of activity can be obtain by dephosphorylation
using phosphatases
 After activation, p38 MAPK targets its substrates
 By phosphorylating them can lead to their
activation or inhibition
p38 MAPK is a kinase with multiple faces
-Inflammation
-Cell cycle regulation
-Apoptosis or cell death
-Proliferation
-Cell differentiation
-Migration
-Survival
-Reactive oxygen spices regulation
-Cytoskeleton maintenance
-Metabolism
-Other???
p38 MAPK is a key player in information delivery
and homeostasis
Why it is important to maintain homeostasis?
Disease
Insulin resistance in
diabetes
Cancer
rheumatoid
arthritis
Inflamatory
reaction
p38 MAPK – good or bad player?
1. Key regulator of cell cycle progression
2. Activation of stress response programm
after stimuly
3. Important in early stages of
embriogenesis, differentiation
4. Act as suppressor of tumorigenesis
(induced cell cycle arrest and cell death)
But!!!
5. Aslo can be involved in increase in
proliferation
Why???
Everything depends on the genetic
background
6. Is involved in angiogenesis
Cancer „addiction”
Normal cell
Cellular
metabolism
Checkpoint
activation
UV light
exposure
Transcriptional
program
activation
Ionizing
radiation
Cytotoxic
treatment
Replication
errors
DNA repair:
BER
NER
MMR
HR
NHEJ
Apoptosis
Single
stranded DNA
damage
Double
stranded DNA
damage
Every of the pathway of DNA repair
has different subpathways (as a
backup)
Cancer „addiction”
Cancer cell
Cellular
metabolism
UV light
exposure
Checkpoint
activation
Ionizing
radiation
Transcriptional
program
activation
Cytotoxic
treatment
Replication
errors
DNA repair:
BER
NER
MMR
HR
NHEJ
Apoptosis
Single
stranded DNA
damage
Double
stranded DNA
damage
How it can be used?
To find a new treatment for cancer – without killing a normal cells
Synthetic lethality
Synthetic lethality arises when a combination of mutations in two or more genes
leads to cell death, whereas a mutation in only one of these genes does not, and by
itself is said to be viable
Synthetic lethality – taking an advantage
during cancer treatment
Oscar story of
BRCA1/2 and PARP
p38 and synthetic lethality?
How to test whether p38 has a synthetic lethal „partner”?
THANKS!
Signalling and Cell Cycle Laboratory