why communication is important – introduction into the world of cell signaling natalia trempolec...

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!