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
Human body
Tissues
Organs
Cells
Complexity of the 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
Controlled
Negative feedback
loop
deviation from a set point causes a response that moves
the system back to the set point
Positive feedback
loop
body senses a change and activates mechanisms that
accelerates that change
Disease
cancer
Metabolic changes
Uncontrolled
Reception
Transduction
Cellular response
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:
- metabolism
- growth and development
- tissue function
- sleep
- mood
System involved:
- nervous - information
- endocrine cell – release of hormons
- bloodstream - transport
- target cell
How cells communicate with each other – introduction into cell signaling
Other factors
Example of endocrine signaling
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
- Signaling molecule protein (also hormone), peptide
- Short distance extracellular enviroment
Examples of autocrine signaling:
- 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
How cells communicate with each other – introduction into cell signaling
Example of autocrine signaling
4. Juxtacrine signaling
- Signaling molecule protein, sugar, lipid, inside the membrane
- Close contactmembrane nanotubes, „bridges”
How cells communicate with each other – introduction into cell signaling
Important facts:
- Cell-to-cell contract is required
- Is important during development and generation of large compact structures
Cancer cell division
Normal cell division
Cell damage DNA damage without repair
Cell commits suicide
Cell damage DNA damage without repair
More DNA damage without repair
Uncontrolled cell division
Why it is important to mantain an equilibrium?
Cancer Cancer cells invade tumor border
Cancer migrationIntravasion of blood system
Arrest extravasion
MicrometastasisProgressive metastasis
and angiogenesis
When everything goes wrong - cancer initiation and metastasis
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
UbiquitinationPhosphorylation
Sumoylation
p38 MAPK is a key player in information delivery and homeostasis
p38 MAPK
Family of protein kinasesPlays 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 p38δSignal transduction is based on posttranslational modification of target protein via phosphorylationAfter phosphosphorylation protein changes its conformation which leads to its activationInhibition 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
rheumatoid arthritis
Inflamatory reaction
Cancer
p38 MAPK – good or bad player?
1. Key regulator of cell cycle progression
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
2. Activation of stress response programm after stimuly
3. Important in early stages of embriogenesis, differentiation
Cancer „addiction”Normal cell
Every of the pathway of DNA repair has different subpathways (as a
backup)
Cellular metabolism
Replication errors
UV light exposure
Ionizing radiation
Cytotoxic treatment
Checkpoint activation
Transcriptional program
activation Apoptosis
DNA repair:
BER
NER
MMR
HR
NHEJ
Single stranded DNA damage
Double stranded DNA damage
Cellular metabolism
Replication errors
UV light exposure
Ionizing radiation
Cytotoxic treatment
Checkpoint activation
Transcriptional program
activation Apoptosis
DNA repair:
BER
NER
MMR
HR
NHEJ
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
Cancer cell
Cancer „addiction”
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
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”?
Signalling and Cell Cycle Laboratory
THANKS!