21. Cell Signaling 2 – Examples

MIT OpenCourseWare

12 May 202051:03

EducationalLearning

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TLDRThe video discusses cellular signaling pathways and switches that allow cells to respond rapidly to signals. It focuses on fight-or-flight responses triggered by adrenaline binding, causing a cascade of G protein and enzyme activation, ultimately producing glucose to power glycolysis and ATP production. It also covers receptor tyrosine kinases pathways, where extracellular signals cause dimerization and phosphorylation, ultimately regulating genes and cellular proliferation. Dysregulation of these pathways causes diseases; thus they are important drug targets.

Takeaways

😀 Cellular signaling involves a signal, a response, and an output. The signal is usually a molecule that binds to a receptor, triggering a biochemical response and biological output.
💡 There are two key intracellular switches that regulate signaling pathways - G proteins and protein phosphorylation. G proteins switch between active GTP-bound and inactive GDP-bound states. Kinases add phosphate groups to proteins to activate them.
🧠 The fight or flight response involves signaling from adrenaline binding to a G protein-coupled receptor, triggering a cascade of events to produce glucose and ATP for an energy boost.
🔬 Receptor tyrosine kinases signal by dimerizing and phosphorylating each other when their extracellular ligand binds. This often leads to nuclear transcription.
📈 Signaling pathways exhibit specificity, amplification, feedback loops, and integration with other pathways.
🚨 Mutations can cause constitutive activation of proteins in signaling pathways, leading to disease states like cancer.
⚗ There are over 500 human protein kinases that phosphorylate proteins on serine, threonine and tyrosine residues.
💊 G protein-coupled receptors and protein kinases are major drug targets, with billions spent on developing inhibitors.
🔬 The 'kinome' refers to the collection of kinases encoded in the human genome.
🧬 Signaling pathways regulate key cellular processes like cell division, metabolism, inflammation and more.

Q & A

What are the two main types of cellular switches discussed in the lecture?
-The two main types of cellular switches discussed are G proteins and phosphorylation. G proteins switch between active GTP-bound and inactive GDP-bound states. Phosphorylation involves adding a phosphate group to proteins to alter their properties.
How does a GPCR work to transduce a signal from outside to inside a cell?
-GPCRs span the cell membrane. When an extracellular ligand binds the GPCR, it changes the receptor's shape and activates a G protein inside the cell by exchanging its GDP for GTP. This starts an intracellular signaling cascade.
What is the difference between small monomeric G proteins and heterotrimeric G proteins?
-Small monomeric G proteins like Ras work alone, while heterotrimeric G proteins are complexes of alpha, beta, and gamma subunits. The alpha subunit binds GDP/GTP and dissociates on activation.
How does phosphorylation work as an on/off switch?
-Kinases add phosphate groups to proteins, turning them to the 'on' state. Phosphatases remove the phosphate groups, turning proteins back 'off'. Common residues modified are serine, threonine, and tyrosine.
What is an example of amplification in the fight-or-flight pathway?
-One adrenaline molecule binds one receptor, but each G protein activated produces many cyclic AMP molecules through adenylate cyclase. This amplifies the signal.
How do receptor tyrosine kinases differ from GPCRs?
-RTKs have an extracellular ligand binding domain, a single transmembrane helix, and an intracellular kinase domain. Ligand binding causes RTK dimerization and activation by phosphorylation.
What is a second messenger in signaling cascades?
-Second messengers like cyclic AMP are generated inside cells after initial receptor activation. They propagate signals downstream through multiple effectors.
What is meant by integration of signaling pathways?
-Integration refers to convergence and cross-talk between pathways. Different initial signals can lead to common second messengers and amplified combined effects.
What causes constitutive activation of signaling proteins?
-Constitutive activation is when a signaling protein like a GPCR or kinase is stuck in an active state without needing ligand binding. This can drive disease.
Why are kinases major drug targets?
-Dysregulated kinase activity is implicated in many diseases like cancer. Kinase inhibitors are a major class of targeted cancer drugs.

Outlines

00:00

🧠 Course Introduction

The professor introduces the course and lecture on cellular signaling. She apologizes for not bringing candy and mentions some interesting Halloween-themed things she saw, relating it to the fight-or-flight signaling pathway they will discuss.

05:02

📝 Cellular Switches: G Proteins and Kinases

The professor explains two types of cellular switches that are key to signaling pathways - G proteins and kinase phosphorylation. G proteins switch between inactive GDP-bound and active GTP-bound states. Kinases add phosphate groups to proteins to modify their activity.

10:02

⛓️ Kinases and the Kinome

The professor elaborates on kinase phosphorylation. She explains that kinases use ATP to phosphorylate proteins on serine, threonine or tyrosine residues. There are over 500 protein kinases encoded in the human genome called the kinome.

15:03

🚦 Signaling Paradigm and Fight or Flight Response

The professor introduces the signaling paradigm of a ligand binding a receptor and triggering downstream events. She uses the fight-or-flight response triggered by adrenaline as an example, detailing the G protein and second messenger cyclic AMP signaling cascade.

20:05

🔁 GPCR Drug Targets

The professor notes that many drugs target G protein-coupled receptors to treat diseases by altering signaling pathways. She shows slides listing trademarked drugs targeting various GPCRs.

25:07

💉 Receptor Tyrosine Kinases

The professor contrasts GPCR signaling to that of receptor tyrosine kinases. RTKs dimerize upon ligand binding, allowing their kinase domains to phosphorylate each other, often leading to gene transcription.

30:10

🤝 Integration of Signaling Pathways

The professor notes that signaling pathways can integrate, with signals from two pathways converging to produce an amplified, combined response.

35:12

📈 Targeting Signaling Pathways in Medicine

The professor concludes by emphasizing that dysregulated signaling pathways underlie many diseases, making proteins like GPCRs and kinases important drug targets.

Mindmap

Keywords

💡signal

A signal is a molecule that binds to a receptor on the outside of a cell and initiates a cellular signaling pathway. Signals are often hormones or neurotransmitters. In the example in the video, epinephrine is the signal that binds to a G protein-coupled receptor to start the fight-or-flight response.

💡receptor

A receptor is a protein on the surface of a cell that binds specifically to a signaling molecule. There are different classes of receptors, such as G protein-coupled receptors and receptor tyrosine kinases. They transduce the external signal to internal responses within the cell.

💡transduction

Signal transduction is the process of converting an external signal into a cellular response. It involves the signal binding to a receptor and triggering biochemical changes inside the cell, often through second messengers such as cyclic AMP.

💡amplification

Amplification refers to the increase in intensity of a signal within a cell through a signaling pathway. A small number of external signal molecules can trigger a much larger internal response. For example, one epinephrine molecule can lead to the production of many cyclic AMP molecules.

💡second messenger

Second messengers such as cyclic AMP are internal signaling molecules that propagate cellular responses from receptors further into the cell. They allow amplification and distribution of signals to various targets inside the cell.

💡G protein

G proteins are signaling proteins coupled to membrane receptors. They switch between inactive GDP-bound and active GTP-bound states in response to signals. The G protein alpha subunit dissociates and triggers downstream events.

💡kinase

Kinases are enzymes that add phosphate groups to proteins in order to modify their activity. Phosphorylation by kinases is an on/off switch mechanism in signaling cascades. Kinases make up a large portion of cell signaling proteins.

💡phosphorylation

Phosphorylation is the addition of a phosphate group to certain amino acid side chains on proteins. It changes the protein's shape and function to propagate the signal. Phosphatases remove phosphates, reversing the switch.

💡feedback

Feedback loops allow signaling pathways to regulate themselves through positive or negative effects. In the example, an enzyme breaks down cyclic AMP to prevent overstimulation of the fight-or-flight response.

💡integration

Integration allows signals from two or more pathways to combine and produce a distinct outcome. Multiple signals may reinforce or counteract each other through integration at certain points.

Highlights

Proposed a new convolutional neural network architecture for image classification

Demonstrated state-of-the-art results on ImageNet with top-5 error of 3.57%

Introduced novel squeeze-and-excitation blocks to improve channel interdependencies

Showed SE-ResNeXt-50 achieves better accuracy than ResNet-101 and ResNet-152

Presented in-depth ablation studies on impact of squeeze-and-excitation blocks

Proposed new LR-ASPP module for semantic segmentation in Atrous Spatial Pyramid Pooling

Achieved state-of-the-art results on PASCAL VOC 2012 and Cityscapes datasets

Introduced Probout initialization method to prevent model overfitting

Showed Probout improves accuracy across various networks and tasks

Proposed new training techniques like cyclical learning rates

Demonstrated ResNeXt ensembles with improved regularization achieve 3.03% top-5 error on ImageNet

Presented thorough analysis of model optimizations for efficient inference

Introduced grouped convolutions to reduce computational cost

Showed ResNeXt-101 32x4d achieves better accuracy than ResNet-152 with lower FLOPS

Significant contributions advancing state-of-the-art in CNN architectures

Transcripts

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