Signal Transduction Lecture Notes PDF

Signal Transduction BMS 531.14 SPRING 2025  Objectives This lecture builds on the introduction to signaling and receptors presented in the previous lecture. It focuses on signal mediation and transduction down a pathway. 1. Identify the corresponding signaling mediators for a given receptor o...

Signal Transduction BMS 531.14 SPRING 2025  Objectives This lecture builds on the introduction to signaling and receptors presented in the previous lecture. It focuses on signal mediation and transduction down a pathway. 1. Identify the corresponding signaling mediators for a given receptor or pathway with particular emphasis on G-coupled protein receptors, inositol triphosphate, integrin signaling, PI3K, and insulin signaling 2. Recognize the steps that lead to signal amplification and explain how low levels of ligand can lead to significant biological responses 3. Explain how signal transduction can be collaborative or concomitant and summarize the conceptual framework of coincident, gated, and feedback mechanisms of signal transduction and apply them using the pathways discussed 4. Assess the consequences for changes in the initiation, propagation, or termination/reset of a given pathway from the perspective of ligands, receptors, mediators, or transcription factors ◦ List the 3 major components to all signaling pathways and explain how alterations to each can lead to adverse consequences LO1, LO2, LO4 Basics of Signal Propagation Point of signaling where amplification occurs Few receptors can trigger several mediators which can then trigger several additional mediators Mediators can be proteins or even ions and phospholipids LO1, LO2, MPP LO4 Callback 2. GPCR: cAMP Signaling Pathway LO3 LO1, LO2, LO4 Metabolism of cAMP cAMP= propagation or signal transduction Propagation = Amplification step ◦ Low levels of ligand activity trigger receptors ◦ Mediators/signal transducers increase the signal at each stage of a cascade Process: ◦ Intramolecular attack of 3’ hydroxyl group of the ribose ◦ Against alpha-phosphoryl group of ATP ◦ Phosphodiester bond ◦ Termination via hydrolysis of cAMP to 5’AMP by cAMP specific phosphodiesterases LO1, LO4 Protein Kinase A Phosphorylates proteins on serine and threonine residues Binds cAMP leading to activation Functions as a mediator ◦ Regulates activity of ion channels and activity of phosphatases that regulate signaling PKA activates molecules such as CREB ◦ Recruits coactivator proteins and induces transcription LO1, LO4 Balancing Stimulation and Inhibition Inhibitory G-proteins behave like stimulatory G-proteins Alpha subunit inhibits adenylate cyclase activation Critical balance Pertussis toxin prevents inhibitory pathway from functioning Cholera toxin prevents GTPase activity LO1, LO4 MPP 2. GPCR: IP3 Signaling Pathway Callback LO3 LO1, LO4 Inositol Signaling and Phospholipase C Can be stimulated by multiple types of receptors Triggers second messengers ◦ Inositol 1,4,5-triphosphate (IP3) ◦ Triggers intracellular calcium stores ◦ Diacylglycerol (DAG) ◦ Activates protein kinase C DAG LO1, LO4 Activity of Mediators INOSITOL TRIPHOSPHATE (IP3) DIACYLGLYCEROL (DAG) The ligand for ligand gated calcium channel Along with calcium activates PKC LO1, LO4 Signaling and Nitric Oxide Synthase Production of reactive nitrogen species can be triggered by calcium via calcium dependent nitric oxide synthase (NOS) Calcium binds to the calmodulin domain in the calcium-dependent NOS NOTE: Binding to calmodulin domains results in conformational shifts to the corresponding protein enabling activation LO1, LO4 Insulin Signaling Insulin receptor is a tyrosine kinase Like most receptors of this type, multiple mediators can be triggered based on specific phosphorylation patterns Insulin signaling can be growth stimulatory (mitogenic) in nature via Ras signaling Phosphatidylinositol3-kinase (PI3K) signaling leads to downstream activation of serine/threonine kinase activity via activation of AKT AKT mediates metabolic effects of insulin in muscle, liver, and adipose LO1, LO4 Integrins Signaling through integrins enables the ECM to influence multiple aspects of cellular behavior Downstream effects include cellular changes in major processes such as migration, proliferation, and differentiation Signaling can be self-promoting as in changing gene expression for more integrins to increase number of receptors Signaling mediation overlaps with other growth stimulatory signaling Vital role in wound healing LO1, LO3, LO4 Collaborative and Concomitant Signaling Integrins demonstrate collaboration and concomitant signaling ◦ Concomitant = signal independently to trigger same molecule ◦ Pathways include: Ras-MAPK, PI3K-Akt, AKT (protein kinase B), and Rho ◦ Collaboration = work together or one activates the other LO1, LO3, LO4 General Mechanisms Review Coincident mechanisms converge at a single unit that leads to output ◦ Detector can differentiate between the pathways and achieve desired corresponding outcome Gated mechanisms represent a regulatory control of one pathway on another (not a literal cell “gate” but that the actions of one pathway contribute to or regulate the other) ◦ Modifies response allowing different responses in a cell-type dependent manner Feedback = modified gated mechanism