2520_F24_L27_Cell signaling_III_preclass

Lecture Overview

• Lecture Title: Cell Signaling III

• Course: BIOL 2520, Cell Biology

• Semester: Fall 2024

• Instructor: Sreeparna Vappala

• Suggested Readings: Chapter 16, pages 577–585

Learning Objectives

• By the end of the lesson, students should be able to:

  • Compare signaling pathways: rapid vs. slower responses (seconds vs. minutes/hours).

  • Identify location and action of second messenger molecules produced by phospholipase C.

  • Explain nitric oxide (NO) as a signaling molecule for smooth muscle cell relaxation.

  • Describe general features of GPCRs and contrast with enzyme-coupled receptors.

  • Explain why NO acts as a paracrine signal.

  • Understand receptor tyrosine kinases (RTKs) activation and their intracellular signaling complex assembly.

  • Discuss the termination of signals initiated by RTKs.

  • List intracellular signaling proteins activated by RTKs and their roles.

  • Explain activation of the MAP kinase signaling module by RTKs.

  • Analyze how Ras contributes to cancer development.

  • Describe how signals that promote growth and survival activate PI-3-kinase pathways.

  • Compare the roles of Akt in cell survival and growth.

Signaling Pathways

• Cyclic AMP Role:

  • Activates protein kinase A (PKA).

  • Different cell types exhibit different responses due to various available target proteins for phosphorylation.

• Cyclic AMP and Gene Expression:

  • Changes in gene expression can take minutes to hours, leading to hormone production.

Inositol Phospholipid Pathway

• Mechanism:

  • G protein activates phospholipase C.

  • Phospholipase C triggers the production of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).

  • IP3 increases intracellular calcium (Ca2+) levels by opening channels in the endoplasmic reticulum.

  • DAG and Ca2+ activate protein kinase C (PKC).

Nitric Oxide Signaling

• Function:

  • NO causes smooth muscle relaxation.

  • Triggered by acetylcholine binding to GPCRs on endothelial cells, leading to NO production and diffusion to smooth muscle cells.

  • Viagra blocks the enzyme that degrades cyclic GMP, enhancing NO's effects.

GPCRs Characteristics

• Features:

  • Speed: Fast responses (e.g., photorector cells respond to light within 20 msec).

  • Sensitivity: Can amplify weak signals.

  • Adaptation: Negative feedback reduces amplification in bright conditions.

Enzyme-Coupled Receptors

• Overview:

  • Possess extracellular ligand-binding domain and cytoplasmic domain that functions as an enzyme or interacts with proteins to mediate cellular responses, including growth and movement.

Receptor Tyrosine Kinases (RTKs)

• Activation Process:

  • Dimerization upon signal binding activates kinase domains, leading to autophosphorylation.

  • Phosphorylated tyrosines serve as docking sites for signaling proteins.

  • Signal termination through phosphatase action or receptor degradation.

Ras Signaling Pathway

• Role of Ras:

  • Small GTP-binding protein activated by many RTKs, oscillating between active (GTP-bound) and inactive (GDP-bound) states.

• Impact: Activation of Ras is crucial in cell proliferation and survival, linking RTK activation to downstream signaling pathways.

PI-3-Kinase–Akt Pathway

• Activation:

  • PI-3-kinase phosphorylates inositol lipids in the plasma membrane, creating docking sites for signaling proteins.

  • Akt (PKB) is activated and promotes cell growth by inhibiting pro-apoptotic factors and stimulating growth pathways like mTOR.

Overview of Multiple Signaling Pathways

• Pathway Interactions:

  • GPCRs activate adenylyl cyclase and phospholipase C.

  • RTKs can activate phospholipase C, Ras, and PI-3-kinase pathways.

  • Activation of various protein kinases leads to different cellular processes crucial for cell function and adaptation.

Conclusion

• The understanding of these signaling mechanisms is crucial for insights into cellular responses, growth, and potential therapeutic interventions.