Chapter 15 - Cell Signaling and Signal Transduction: Communication Between Cells

3 main types of intercellular signaling

1. autocrine

2. paracrine

3. endocrine

Autocrine signaling

cell responds to its own signal

Paracrine signaling

short-range signaling between nearby cells

Endocrine signaling

long-range signaling via the bloodstream

Signal transduction

cascade where one protein changes the enxt to relay and amplify a message that alters cell activity

How do proteins change others typically in signal transduciton?

by phosphorylation

What enzymes add and remove phosphates in signaling?

kinases: add

phosphatases: remove

Common effects of protein phosphorylation

1. activation of enzymes

2. interaction/location alterations

3. trigger degradation

4. change function depending on cell type

G-protein-coupled receptors (GPCRs) structure

seven transmembrane alpha-helices that interact with hetertimeric G proteins (a, b, g)

GPCRs activation

1. ligand binding

2. receptor shape change

3. GPD on Ga replaced with GTP

4. Ga dissociates form Gbg

5. Activates effector enzyme

What ends GPCR signaling?

Ga hydrolyzes GTP —> GDP; RGS proteins accelerate this hydrolysis

Desensitization

GRK phosphorylates active receptors; arrestins bind phosphorylated GPCRs, preventing further G protein activation

Resensitization

after internalization, GPCRs can be dephosphorylated and recycled back to the membrane

Receptor Protein-Tyrosine Kinases

single-pass membrane proteins with cytoplasmic kinase domain

Ligand-Gated Ion Channels

Ion flow changes membrane potential

Steroid Hormone Recepotrs 

Cytoplasmic or nuclear ligand-regulated transription factors

Immune receptors

B- and T-cell receptors

Second Messenger

Small intracellular molecule that amplifies a signal from a first messenger (ligand)

Common second messengers

1. cAMP

2. Ca2+

3. IP3

4. DAG

5. cGMP

6. NO

How is cAMP produced?

ligand —> GPCR —> Ga activates adenylyl cyclase —> ATP —> cAMP

What does cAMP activate?

protein kinase A

Protein Kinase A

phosphorylates target proteins to alter metabolism after gene expression

What hormones raise blood glucose via cAMP?

glucagon and epinephrine

Describe the cascade

1. hormone binds receptor

2. Ga activates adenylyl cyclase

3. cAMP

4. PKA

5. phosphorylase kinase

6. glycogen phosphorylase

7. glucose release

Why is this cascade so powerful?

each step amplifies the signal, so one hormone molecule can release thousands of glucose units

What do protein-tyrosine kinases do?

phosphorylate tyrosine residues on target proteins to trigger signaling pathways

Two classes of PTKs

1. receptor PTKs

2. non-receptor (cytoplasmic) PTKs

How are RTKs activated?

1. ligand binding

2. receptor dimerization

3. trans-autophosphorylation of tyrosines on each other’s cytoplasmic domains

What do SH2 and PTB domain proteins do?

Bind phosphorylated tyrosines

What do SH2 and PTB domain proteins function as?

Adaptors, docking proteins, signaling enzymes, or transcription factors

How is RTK signaling terminated?

Receptor internalization via clatrhin-mediated endocytosis and ubiquitin tagging for lysosomal degredation/recycling

What is Ras?

A small GTPase anchored to the plasma membrane; switches between active GTP and inactive GDP forms

How is RAS activated?

RTK —> adaptor Grb2 —> GEF (Sos) —> GDP —> GTP exchange on Ras

What enzymes control Ras activity?

1. GAPs

2. GEFs

3. GDIs

GAPS

accelerate GPT hydrolysis (off)

GEFs

stimulate GDP —> GTP (on)

GDIs

hold GDP-bound Ras inactive

Describe the MAP kinase cascade

Ras —> Raf —> MEK —> ERK —> transcription factors —> gene expression for cell growth & differentiation

Why is RAS clinically important?

Mutations that prevent GTP hydrolysis keep Ras active —> uncontrolled cell division —> 30% of cancers

Convergence

different receptors activate the same pathway

Divergence

A single stimulus sends signals through multiple pathways to produce different responses

Cross-talk

interaction between signaling pathways

Apotosis

orderly cell-death process

What does apoptosis cause?

• cell shrinkage

• loss of adhesion

• DNA fragmentation

• phagocytic clearance

What enzymes execute apoptosis?

Caspases (proteases) that cleave key proteins like kinase, lamins, cytoskeletal proteins, and CAD (DNase)

Why is apoptosis important in development and health?

• shapes organs

• removes damaged cells

An imbalance caused by apoptosis leads to

cancer or neurodegenerative disease