Lecture+4_Signal+Transduction_Upload.pptx

Optional accompanying reading Pharmacology 4001: Mechanisms of Drug Action Chapter 15 Lecture 4: Signal Transduction, Part I January 25, 2024 Signal Transduction, Part I Optional accompanying reading: Chapter 15 Figure 15-8 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular...

Optional accompanying reading Pharmacology 4001: Mechanisms of Drug Action Chapter 15 Lecture 4: Signal Transduction, Part I January 25, 2024 Signal Transduction, Part I Optional accompanying reading: Chapter 15 Figure 15-8 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” fourth edition 2002,.Garland Science Signal Transduction, Part I Accompanying lecture notes now available on Canvas Passage through the G1 checkpoint occurs in response to signals Figure 17-41 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” fourth edition 2002, Garland Science. “The Cell Cycle” Lecture “Transcription Regulation” Lecture Today! Start of ”Signal Transduction” How the cell knows the answer to “Is the environment favorable?” Learning Objectives 1. Name the simplified components of a signaling pathway. 2. List and describe the different types of signaling. 3. Describe the characteristics of second messengers. 4. How are second messengers generated and inactivated? Signal Transduction: An Overview Figure 15-8 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” fourth edition 2002,.Garland Science Not all cells respond the same way to the same signal Figure 15-5 Molecular Biology of the Cell (© Garland Science 2008) Types of Signaling (E) Autocrine! Figure 15.4 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” fourth edition 2002, Garland Science Let’s discuss – How do these relate to cancer? A Simplified View of Signaling #1 1. Signal molecule (first messenger) 2. Receptor protein 3. Intracellular signaling proteins (second messengers or kinases) 4. Target proteins #2 #3 #4 Figure 15.1 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” fourth edition 2002,.Garland Science A focus on plasma membrane receptors Many receptors are transmembrane proteins on the target-cell surface. When these proteins bind an extracellular signal molecule (a ligand), they become activated and generate various intracellular signals that alter the behavior of the cell. In other cases, the receptor proteins are inside the target cell, and the signal molecule has to enter the cell to bind to them: this requires that the signal molecule be sufficiently small and hydrophobic to diffuse across the target cell’s plasma membrane Today we will focus primarily on signaling through cellsurface receptors but know that not all receptors are located on the plasma membrane, they can be on the membranes of other organelles (e.g., mitochondria, Binding of a ligand to a receptor Many signal molecules act at very low concentrations, and their receptors usually bind them with high affinity (dissociation constant Kd ≤ 10–8 M) – 10–8 M = 10 nM We’ll talk more about ligand binding to a receptor in future classes Kinase signaling cascades Many intracellular signaling proteins controlled by phosphorylation are themselves protein kinases, and these are often organized into kinase cascades. In such a cascade, one protein kinase, activated by phosphorylation, phosphorylates the next protein kinase in the sequence, and so on, relaying the signal onward and, in some cases, amplifying it or spreading it to other signaling Figure 15.17 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P pathways. Walter “Molecular Biology of the Cell” fourth edition 2002, Garland Science Advantages of a Cascade Regulation Amplification Figure 15.17 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” fourth edition 2002, Garland Science Signaling Vocabulary  First messenger = neurotransmitter, hormone, peptide, what initially binds the receptor, often extracellular  Second messenger = small molecule that ‘transduces’ the signal from the receptor to an effector protein  Note, a small molecule is < 900 daltons and is not composed of amino acids  ~12 second messengers  Cells mix and match second messengers with different receptors and effectors to explain a lot of signal transduction. Figure 15.16 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” sixth edition 2014, Garland Science Major Sources of Second Messengers  Membrane-derived second messengers  Nucleotide triphosphates  Ion gradients Major Sources of Second Messengers  Membrane-derived second messengers  Nucleotide triphosphates  Ion gradients Major Sources of Second Messengers  Membrane-derived second messengers  Nucleotide triphosphates  Ion gradients What do all of these sources have in common? Rapidly formed from readily available precursors allowing for quick response Readily reversible Phospholipid-derived second messengers Phospholipid-derived second messengers: IP3 and DAG Figure 15.28 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” sixth edition 2014, Garland Science One signaling pathway can involved multiple second messengers Figure 15.26 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” sixth edition 2014, Garland Science Calcium changes the activity of many targets, not just PKC A short transducer half-life is important Allows for rapid response to a changing environment. Figure 15.14 of B Alberts, A Johnson, J Lewis, M Raff, K Roberts and P Walter “Molecular Biology of the Cell” sixth edition 2014, Garland Science How are second messengers inactivated? Phosphodiesterases (cAMP, cGMP) Ion transporters (Ca+2, Na+, K+) Enzymatic inactivation (prostaglandins, IP3, diacylglycerol) Note that these can all happen quickly – You don’t have to wait for ubiquitination and degradation How are other transducers (e.g., kinases) shut off? Phosphatases! Also fast, no degradation. Learning Objectives Revisited 1. Name the simplified components of a signaling pathway. 1. 2. 3. 4. Signal molecule (first messenger) Receptor protein Intracellular signaling proteins (second messengers or kinases) Target proteins 2. List and describe the different types of signaling. 1. 2. 3. 4. 5. Endocrine signaling depends on endocrine cells, which secrete hormones into the bloodstream for distribution throughout the body. Paracrine signaling depends on local mediators that are released into the extracellular space and act on neighboring cells. Autocrine signaling occurs when a cell secretes a signaling molecule that binds back to its own receptors. Contact-dependent signaling requires cells to be in direct membrane–membrane contact. Synaptic signaling is performed by neurons that transmit signals electrically along their axons and release neurotransmitters at synapses 3. Describe the characteristics of second messengers. Small molecules Rapidly generated Generated from readily available sources (e.g., ion gradients, plasma membrane phospholipids) Readily reversible (i.e., can be turned off quickly by phosphodiesterases or ion transporters. 4. How are second messengers generated and inactivated? They are generated from readily available sources, including bembrane sources (IP3, DAG), nucleotide sources (cAMP, cGMP), ion gradients (Ca+2, Na+, K+), They are inactivated by phosphodiesterases (cAMP, cGMP), ion transporters (Ca+2, Na+, K+), enzymatic inactivation (prostaglandins, IP3, diacylglycerol) Homework Assignments for Jan 16 – Feb. 13 Complete Quiz #4 by Tuesday at 9:05 am. On Canvas. Two attempts. Download REVIEW ARTICLE #1: Hanahan, D., and R. A. Weinberg (2000). The hallmarks of cancer. Cell 100, 57-70. – Start reading and prepare to discuss during lecture on Feb. 1 Download RESEARCH PAPER #1: Druker at al. (1996). Effects of a specific inhibitor of the Abl tyrosine kinase on growth of Bcr-Abl positive cells. Nature Medicine 2, 561-564. – Start reading and prepare to discuss during lecture on Feb. 13