Introduction to Signaling Networks

Biophysics 702, February 2012Jonathan P Butchar

Intracellular and Intercellular signaling

• General Signaling Concepts• Types of Signaling• Initial Signaling Components

– Receptors– Ligands

• Downstream Signaling Components– Kinases– Phosphatases– Adaptors & Effectors

General Signaling Concepts

Figure 15-8 Molecular Biology of the Cell (© Garland Science 2008)

Signaling is multifaceted and dynamic

• Different outcomes, even from a single signal– e.g., Strength of signal

• Convergence of signals• Crosstalk between pathways• Cells can adapt over time

– dampened or heightened responses

• Signals can be amplified or dampened via feedback

• Primary versus secondary responses

Types of Signaling

Numerous ways to signal

• Contact-dependent• Autocrine / Paracrine• Endocrine• Direct Transmission (gap junctions)

Initial Signaling Components• Receptors and Ligands

Receptors

• Cell surface• Intracellular

Ligands

• Peptides / Proteins• Steroids• Nucleotides• Fatty Acids• Gases• Mechanical Forces• …etc

How are these signals transmitted?

• Ion fluxes• G-protein activation• Enzyme activation (e.g., Phosphorylation)

Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)

Example: Receptor Tyrosine Kinases

Downstream Signaling Components

• Kinases• Phosphatases• Adaptors• Effectors

What molecules transmit the signals?

• Kinases add phosphate groups• Phosphatases remove these phosphates• Guanosine Tri-Phosphate / GDi-P cycles

drive many signaling cascades• Adaptors help bring necessary molecules

together• Effectors generate the responses

– commonly gene transcription

Figure 15-18a Molecular Biology of the Cell (© Garland Science 2008)

Kinases and phosphatases

e.g., Receptor Tyrosine Kinase: a receptor AND a kinase

Figure 15-18b Molecular Biology of the Cell (© Garland Science 2008)

Guanosine TriPhosphate and Guanosine DiPhosphate

e.g., G-protein coupled receptor

Figure 15-32 Molecular Biology of the Cell (© Garland Science 2008)

Trimeric G-proteins

• 3 subunits– α, β, γ

…another view, from WikipediaActivated when GTP replaces GDP, inactivated when GTP is auto-hydrolyzed to GDP

Figure 15-19 Molecular Biology of the Cell (© Garland Science 2008)

Monomeric G-proteins

• Most well-known is Ras– small GTPase– downstream Raf binds

only GTP-Ras, which phosphorylates and hence activates Raf

GTPase-activating protein

Guanine nucleotide exchange factor

Figure 15-22 Molecular Biology of the Cell (© Garland Science 2008)

Adaptor and Scaffold proteins have characteristic domains

• SH2 binds phosphotyrosine

• SH3 binds proline-rich domains

• PH binds phosphoinositides

Proline-rich

How proper localization is achieved

• Association at plasma membrane• Scaffolding proteins• Direct receptor binding

Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)

Signaling Example: from G-proteins to gene

transcription

• Activated receptor• Activated G-protein• Activated Protein Kinase A• The Effector, an activated

transcriptional modulator

Lines are blurry at times

• Some membrane-bound receptors can go to the nucleus and regulate gene transcription– Both a receptor and an effector

• Phosphorylation can sometimes deactivate rather than activate a protein

Summary

• Cells and groups of cells possess mechanisms to generate and respond to signals

• Signaling can be autocrine, paracrine, endocrine, synaptic, electrical or mechanical

• Receptors sense numerous types of stimuli and begin cascades that lead to cellular responses

• Observed responses represent an integration of numerous stimuli, both past and present