Cell Signaling Lecture Notes

Cell Signaling

Cells coordinate functions within multicellular organisms for:

• Embryonic development (cellular differentiation).

• Maintenance of homeostasis.

• Communication between and within tissues/organs.

How cells receive and interpret signals: Cell Signaling.

Signal Transduction

• Different forms of signals carry the same information (e.g., telephone: electrical impulses turned into sound).

• Conversion of information from one type to another = signal transduction.

• Important concept in cell signaling.

Types of Cell Signaling

Signaling cell -> Target Cell (via cell receptor).

Signals are sent by:

• Hormones (endocrine signaling).

• Signal molecules (paracrine/autocrine signaling).

• Electrical impulse (neuronal signaling).

• Cell contact (contact-dependent signaling).

• Endocrine, Neuronal - short/long distances

• Paracrine/Autocrine, Contact - short distances

Autocrine Signaling Conditions

• A single signaling cell receives a weak autocrine signal.

• In a group of identical signaling cells, each cell receives a strong autocrine signal.

Cellular Response to Signals

• Each cell encounters 100s of different signals.

• Cells respond selectively only if they have a receptor for that signal.

• Cells regulate the number and availability of receptors to regulate responsiveness.

• One signal and its receptor proteins can have a variety of effects within an individual cell and between different cells.

Examples of Acetylcholine Signal

• Heart muscle cell: Decreased frequency of contraction.

• Salivary gland cell: Secretion.

• Skeletal muscle cell: Contraction.

Acetylcholine molecular formula: $CH<em>3-CO-O-CH</em>2-CH<em>2-N(CH</em>3)_3$

Signal Combinations and Receptors

• Cells possess a variety of receptors (dozens on each cell).

• Signals may act simultaneously.

• Combinations of signals are required to evoke a response.

Roles of Signaling Cascades

• Transfer signal to cellular machinery to elicit response.

• Transform the signal into a form to stimulate response (transduction).

• Amplify signal to evoke larger response (cascade).

• Distribute signal to influence several processes in parallel (divergence).

• Provide means to manipulate the response (modulation factors).

Steps of Signaling Cascades

• Primary Transduction

• Relay

• Transduce and Amplify

• Integrate

• Distribute

Relay Effect

• Growth factor binds to Receptor PTK.

• Receptor binds to Grb2 and Sos.

• Ras-GDP converts to Ras-GTP.

• MAPKKK (Raf) is activated which activates MAPKK, which in turn activates MAPK.

• MAPK activates TF (transcription factor).

• Gene Transcription occurs.

Amplification Process

1. One molecule of signaling ligand.

2. Each activated receptor protein may activate many molecules of G protein.

3. Each $G_\alpha$ subunit that can activate an adenylyl cyclase molecule for a prolonged period.

4. Each activated adenylyl cyclase molecule generates many cAMP molecules.

5. cAMP molecules activate A-kinase.

6. Each A-kinase molecule can phosphorylate and thereby activate many copies of enzyme X.

7. Each copy of enzyme X produces many molecules of product.

Divergence

• cAMP activates Kinase:

  • Targets Plasma membrane (transport).

  • Targets Microtubules (assembly/disassembly).

  • Targets Endoplasmic reticulum (protein synthesis).

  • Targets Nucleus (DNA synthesis, differentiation, RNA synthesis).

• Kinase targets:

  • Triglyceride lipase (lipid formation).

  • Glycogen synthase.

  • Phosphorylase kinase (glycogen formation).

  • Phosphorylase (glycogen breakdown).

Integration/Modification of Signals

• EGF receptor interacts with growth factor.

• Epinephrine interacts with Receptor.

• SH2 binds to Ras, which interacts with GTP, Sos, and Grb2.

• MAPKK activates Raf, which activates MAPK and Transcription factor, leading to Gene activity.

• cAMP activates PKA.

Cell Surface Receptors

How do receptors transduce signals?

• Ion-channel-linked receptors.

• G-protein-linked receptors.

• Enzyme-linked receptors.

• Number of different types of receptors > number of signals that act on them.

• Many drugs or poisons act by blocking or overstimulating receptors.

Ion-Channel-Linked Receptors

• Binding of the signal molecule opens the ion channel.

• Results in alteration in membrane potential.

• Regulation of transport of other small molecules (ions).

G-Protein-Linked Receptors

• Signal from receptor passed to a GTP binding protein (G-protein).

• Activated G-protein can then in turn activate an enzyme by GTP hydrolysis.

• Enzyme to be activated is the membrane-spanning receptor itself.

• Activation by ligand binding = altered conformation.

G-Protein-Linked Receptors Structure

• Largest family of cell-surface receptors.

• Mediate response from hormones, local mediators & neurotransmitters.

• All have similar structure:

  • Single protein crosses bilayer 7 times.

  • Cytoplasmic portion (binds G-protein).

  • Ligand-binding domain.

G-Protein Activation Process

1. Inactive G protein and receptor protein.

2. Signal molecule binds to the receptor.

3. GDP is exchanged for GTP, activating the $G<em>\alpha$ subunit and $G</em>\beta\gamma$ complex.

4. Activated G-protein subunits separate and can activate downstream targets.

Secondary Messengers

• Enzyme activated by G-Proteins catalyzes the synthesis or activation of messenger molecules (Secondary messengers).

Enzyme-Linked Receptors

• Transmembrane proteins with:

  • Ligand-binding domain.

  • Possesses enzyme activity.

• Responses typically slow (~hrs).

Receptor Tyrosine Kinase

• Most common class - receptor tyrosine kinase.

• Upon activation, it can phosphorylate its own tyrosine residues:

  • Binding/activation of signaling molecules (secondary messengers).

Fast & Slow Response

• Fast - altered protein function (sec-min).

• Slow - altered gene expression (min-hrs).

Signal Integration

Different signals can converge to activate the same downstream signaling components by phosphorylation.

Adaptation

• Adaptation = increase sensitivity / decrease sensitivity

• Determine the same % change in response regardless of magnitude.

• Achieved by receptor:

  • 'Down regulation'.

  • 'Up regulation'.

• Receptors are modified to alter sensitivity to external signal.

Signal Adaptation Mechanism

1. Rise in cyclic AMP activates A-kinase to phosphorylate receptor at a single site.

2. B-adrenergic kinase phosphorylates activated receptor at multiple sites.

3. $\beta$ arrestin binds to phosphorylated receptor.