Cell Signaling

2007

• Cells sense and send information (signals)• Cells communicate with each other• Cells must sense and respond to changes in

the environment

The signal can come from inside the cell, from another cell, or from the environment.

©2004 Lee Bardwell

Cell Signaling

Generic Signaling Pathway

Signal

Receptor (sensor)

Transduction Cascade

OutputSomething

happens

outside

inside (cytosol)

©2002 Lee Bardwell

Something

happens

Responses to cell signaling

• Gene expression is altered at the level of transcription, RNA processing or translation

• Enzyme activities are altered• Protein-protein interactions are induced or

inhibited• The localization of certain proteins and other

stuff is altered

biochemically

©2002 Lee Bardwell

Something

happens

Responses to cell signaling

The Cell…– divides or stops dividing– differentiates– commits suicide or kills something– moves somewhere or stops moving– alters its metabolism– passes on the signal

Physiologically

©2002 Lee Bardwell

What can be a signal?- almost anything

• Peptides - insulin, glucagon...• Proteins• Amino acid derivatives - epinephrine, histamine• Other small biomolecules - ATP• Steroids, prostaglandins• Gases - Nitric Oxide (NO)• Photons• Damaged DNA• Odorants, tastants

©2002 Lee Bardwell

Steroid Hormone Signaling Pathway

Signal

(steroid)

Receptor (txn factor)

Steroid Hormone Signaling Pathway

Output

∆ gene expression

∆ cell physiology

Signaling cascades have many steps

Past:Enumeratecomponents

Now:• Modules• Circuits/ Design Logic• Cross-talk• Specificity

Adrenaline signaling

• Signal: Adrenaline (epinephrine)– Secreted by adrenal gland

• Receptor: -adrenergic receptor

• Response:– Breakdown of glycogen to glucose to

provide energy for “fight-or-flight”

Insulin signaling

• Signal: insulin– Secreted by cells of pancreas

• Receptor: a receptor kinase• Response:

– Sugar is taken up from bloodstream into cells

• Diabetes - type 1, type 2

Growth factor signaling

The growth of multicellular organisms is regulated by more than just nutrient availability

NUTRIENTS

NUTRIENTSunicellulareukaryote

multicellulareukaryote

a edigner

Cells in multicellular eukaryotes require permission signals from growth factors

NUTRIENTS

NUTRIENTS

a edigner

Disregulation of growth factor signal transduction leads to cancer

NUTRIENTS

cellulartransformation

NUTRIENTS

Some growth factors

• EGF - epidermal growth factor

• FGF - fibroblast growth factor

• NGF - nerve growth factor

• PDGF - platelet-derived growth factor

• Insulin-like GF

All of these bind to a class of receptors known as “Receptor Kinases”

Receptors with enzymatic activity

Protein kinases and phosphatases

- Add/remove phosphates to/from proteins

- Involved in all signaling from cell surface recetors, and in most other signaling too

©2002 Lee Bardwell

Protein Kinase Reaction

Kinase

Substrate

P P PPATP

P P P

Protein Kinase ReactionPhosphorylation of protein substrates

Product

Phosphorylation can flip a protein from “active” to “inactive” or vis-versa

ATP

ADP

RAF

MEK

MAPKMAPK

TXY TXY

MEKPP

PP

P P

SP TP SP TP

The Mitogen-Activated Protein Kinase (MAPK) Cascade

Neoplastic phenotype

Ras

MEKK

MEK/MAPKK

MAPKs

Raf

receptor

growth factor

MEK1

ERK1 ERK2

MEK2

Elk1/SRF

HER2

Fos Jun

FOS

CCND1

cyclin D1

How do protein kinases

recognize their protein

substrates ?

Specificity in MAPK Signalling

Protein Kinase Reaction

Kinase

Substrate

P P PPATP

P P P

Protein Kinase ReactionPhosphorylation of protein substrates

Product

Active site - target peptide interaction is not enough for

specificity

Kinase

Substrate

Tethering function:Tethering function: Grewal et al (2006) Cell. Grewal et al (2006) Cell. Signal. 18:123Signal. 18:123

Bardwell Lab

• Lee Bardwell• Jane Bardwell• Kandarp Shah• Lamar

Blackwell• Tom Whisenant• Jeff Rogers• Pascal Krotee