Chapter 6: Cell Signaling PDF

Republic of the Philippines **TARLAC STATE UNIVERSITY** **COLLEGE OF TEACHER EDUCATION** Lucinda Campus, Tarlac City Tel. no (045)4930182; Fax No. (045)982-0110 **What is cell and signaling?** 1. **What is cell?** - biology, a cell is the basic structural and functiona...

Republic of the Philippines **TARLAC STATE UNIVERSITY** **COLLEGE OF TEACHER EDUCATION** Lucinda Campus, Tarlac City Tel. no (045)4930182; Fax No. (045)982-0110 **What is cell and signaling?** 1. **What is cell?** - biology, a cell is the basic structural and functional unit of living organisms. It is the smallest unit of life and can perform all the essential functions required for survival, such as metabolism, energy production, and reproduction. 2. **What is Signaling?** - Signaling\" refers to the process of sending or transmitting information from one entity to another, often in a way that facilitates communication, coordination, or response. **KEY CONCEPT IN CELL SIGNALING** - Signal Transduction -Signal transduction refers to the molecular cascade that begins when a signaling molecule (ligand) binds to a receptor and ends with a specific cellular outcome. This process amplifies the initial signal and translates it into functional actions within the cell. - Receptors - Signal Amplification - Second Messengers - Effector Proteins **CELL SIGNALING AND SIGNAL TRANSDUCTION DIFFERENCE AND CONNECTION ** **Cell Signaling** -a broad term that encompasses the entire process by which cells communicate, including the sending, receiving, and processing of signals. **Signaling Transduction** -specific sub-process within cell signaling that describes the intracellular signaling events triggered after a receptor binds a ligand. **SIGNAL TYPES** **There are four major types of cell signaling.** - AUTOCRINE -a **signaling molecule acts on the same cell that produced it.** cell releases signaling molecules that bind to receptors on the same cell that released them. - ENDOCRINE \- Hormones are released into the bloodstream and travel long distances to act on distant target cells. PARACRINE \- Signaling molecules are released by a cell and affect nearby target cells - JUXTACRINE \- Cells communicate through direct physical contact, with signaling molecules on the surface of one cell interacting with receptors on an adjacent cell. **SIGNAL AMPLIFICATION ** \- Signal amplification refers to the process by which a small initial signal is greatly increased or magnified within a cell, leading to a stronger and more widespread cellular response. **SIGNALING PATHWAYS** \- Signaling pathways refer to the series of molecular events that occur inside a cell after a signaling molecule (ligand) binds to a receptor on the cell\'s surface or inside the cell **Cellular Response** it is essential processes that enable cells to adapt to their environment and maintain health. - **CELL SIGNALING - Receptors for Cell Signals** **CELL SIGNALING ** -  The process by which a cell responds to substances outside the cell through signaling molecules found on the surface of and inside the cell. **RECEPTOR** -  Cellular receptors are protein inside a cell or on its surface which receive a signal. In normal physiology, this is a chemical signal where a protein-ligand binds a protein receptor. **2 TYPES OF RECEPTORS ** 1. **INTRACELLULAR RECEPTOR** --  are soluble cytoplasmic or nuclear proteins that are activated by molecules that can pass through the plasma membrane of the cell. 2. ** CELL SURFACE** - also known as transmembrane receptors, are proteins that are embedded in the plasma membrane of cells and act as signal transducers in cell signaling.  **3 Major Classes of Membrane Receptors** 1. **G-Protein Coupled Receptors** -- g protein-coupled receptors (GPCRs) are integral membrane proteins containing an extracellular amino terminus, seven transmembrane α-helical domains, and an intracellular carboxy terminus. 2. **Ligand Gated Ion Channel** - are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane. 3. **Receptor Tyrosine Kinases** - play an important role in many cell functions, including cell-to-cell communication and cell division, maturation, movement, metabolism, and survival. - SIGNALING AT CELL'S SURFACE  Types of Receptors Receptors  - Protein molecules that bind with specific molecules called Ligand.  Ligand  - Specific molecules (Hormones, Neurotransmitter, etc.) - Primary messengers  Two Types of Receptors  1. Internal Receptors  - Also known as intracellular or cytoplasmic receptors.  - Can be found in cytoplasm or nucleus.  - They respond to hydrophobic ligand  2. Cell-surfaced Receptors  - Also known as transmembrane receptors  - Proteins that are attached to cell membrane  - It has three types of receptors  a. Ligand Gated Ion Channels Receptors  - Transmembrane receptors that act as ion channels that can open in response to ligand-receptors binding.  *Structure*: Proteins in cell membranes *Activation*: Binding of Ligand to the channel's receptor site.  *Conformational change*: Ligand-Receptor complex change the channel\'s shape and produce a cell signal.  *Ion flow*: Ions such as (Na+, Ca+, K+, Cl+) allows to travel through the channel.  b. **G Protein - Coupled Receptors** - G-protein (guanine nucleotide binding protein)  or known as heterotrimeric. - GDP (Guanosine diphosphate) are the off switch.  - Alpha subunit holds the GDP and GTP - GTP (Guanosine triphosphate) are the on switch  A diagram of a structure Description automatically generated *Structure:* categorized by 7 membranes and the tail where the g-protein (heterotrimeric) is attached.  *Mechanism of Action: * *Resting State:* Before the signaling  *Activation:* Ligand binds to receptor causing the G-protein to be activated.  *GDP-GTP exchange:* a-subunit release GDP and pick up GTP  *Subunit Separation:* a-subunit will dissociate to β, γ subunits *Targeted Protein Activation:* a-subunit will activate adenylate cyclase to produce secondary messenger (cAMP -- cyclic adenosine monophosphate)  *Signal Termination:* a-subunit breaks down GTP to GDP through hydrolysis and eventually a-subunit will reassociate to β, γ subunit.  *Reset:* GPCR will return to its resting phase and ready for the next signal.  c. **Enzyme-linked Receptors ** - also known as a catalytic receptor - binding of an extracellular ligand causes enzymatic activity on the intracellular side - there are many types of ELR but the most common is Receptor Tyrosine Kinases  - Receptor Tyrosine Kinases   *Structure*: Single transmembrane proteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. *Activation:* Ligand binding induces receptor dimerization. *Dimerization:* pairing up two receptors  *Tyrosine Phosphorylation*: Dimerization activates the intracellular kinase domains, leading to the phosphorylation of tyrosine residues on the receptors. *Signal Transduction*: Phosphorylated tyrosine residues serve as docking sites for signaling proteins that initiate intracellular signaling cascades. *Cellular Responses*: Activation of pathways influencing cell growth, differentiation, survival, and proliferation. - **Agonist vs.  Antagonist ** - Agonist Drugs  - molecules that can bind and activate a receptor to induce a biological reaction.  - Example: Morphine will bind to a receptor and it will produce pain relief or euphoria to our body. - Full Agonist  - display high efficacy for activating receptor function. Thereby inducing the complete response capable of that receptor.  - Partial Agonist  - These can bind to a receptor but only elicit a partial biological response, meaning they activate the receptor to a lesser extent than full agonists - Example: Morphine will only have a partial effect on our body.  - Antagonist Drugs  - Antagonists may bind to the specific receptor in the brain, but produce no response preventing the natural signal molecule or other agonists from binding and activating it - Example: Naloxone is an antagonist for opioid receptors. It blocks these receptors, preventing opioids from binding and reversing their effects. - Competitive antagonists  - Agonist and antagonist compete for the binding site  - The higher the concentration of antagonists, the higher the chance for them to occupy the binding site and vice versa  - Non-competitive antagonists - bind to a site other than the agonist\'s binding site (allosteric site) antagonist stops agonist to produce cell response despite of having a higher concentration - **Cell Binding and Cell Activation** **Cell binding:** The interaction between cells through surface receptors and molecules. **Types of cell binding** 1. **Receptor- Ligand Binding** - It is when a molecules or ligand attached to a specific protein inside the cell or the receptor.  **2 types of ligand binding site:** **Specific Binding-** Is the direct interaction at a specific or active site on the molecules. **Allosteric Binding-** Occurs at a different site and modulates the molecules function through conformational change. 2. **Cell- Cell Adhesion** - Refers to the process by which cells interact and attached to neighboring cells using specialized molecules. **2 types of cell- cell adhesion** **Homophilic Binding-** Same type of cell bind to each other **Heterophilic Binding-** Different types of cell bind to each other **4 types of Cell adhesion molecules** **Cadherins-** helps same type of cell stick together to form tissue **Integrins**- helps cells attached to the surrounding environment like the extracellular matrix. **Selectins**- helps cell moves and stick to blood vessels walls, especially during immune response. **Immunoglobulin Superfamily-**  it helps cell stick together especially in immune function like inflammation. In short cell adhesion molecules act as a glue to keep cells connected and support tissue structure. 3. **Antigen- Antibody Binding** - Specific binding where an antibody bonds to an antigen, typically at the antigen epitopes. **Mechanism of Cell Binding** 1. **Lock and Key mechanism** - Where the ligand bind to the specific receptor. Where the ligand fits to its receptor. 2. **Induced Fit Model** - The receptors binding site undergoes to slight conformational change upon ligand binding to improved the fit, unlike the lock and key model where the ligand fits perfectly from the start.  **Cell Activation:** The process that occur after binding, leading to a change in the cell\'s state, such as gene expression, movement or secretion. **Lymphocytes:** A type of white blood cell that part of immune system **2 types of lymphocytes.** **T Cell-** Responsible for the recognition of antigen **B Cell-** Responsible for the clonal expansion of B cell. - **NOTCH SIGNALING** HISTORY - Discovered by Thomas Hunt Morgan in 1917 in Drosophila Melanogaster. - Linking Notch to Development in Humans proposed by Donald F. Poulson (1985). - Discovery of Notch Pathway by Spyros Artavanis-Tsakonas. WHAT IS NOTCH SIGNALING? - A conserved cell communication pathway that influences cell fate. *Mechanism:* - Lateral Inhibition - how cells decide different roles. - Contact-Based Signaling - how they need to touch to send the message. The **Notch Receptor** is a large, single-pass transmembrane protein, meaning it crosses the cell membrane once. *Four Types of Notch Receptor:* Notch1 Notch2 Notch3 Notch4 The structure of a Notch receptor has several key regions: - Extracellular Domain - This is the part of the receptor that extends outside the cell. - EGF-like repeats - Lin12-Notch repeats (LNR) - Transmembrane Domain - This is a short segment that anchors the receptor within the cell membrane. - Intracellular Domain (NICD) - The NICD is the part of the receptor inside the cell. When the receptor binds to a ligand, the NICD is cleaved and released into the cell, where it travels to the nucleus to influence gene expression. - RAM Domain & ANK Repeats - Nuclear Localization Signals (NLS) - Transactivation Domain (TAD) - PEST Domain **Ligands** are also transmembrane proteins, meaning they're anchored in the membrane of neighboring cells. *The main Ligands are:* Jagged1 & Jagged2 Delta-like 1 (DLL1), Delta-like 3 (DLL3), & Delta-like 4 (DLL4) Key parts of the Ligands' structure include: - Extracellular Domain - This part of the ligand extends out of the cell and interacts with the Notch receptor's extracellular domain. - Delta-Serrate-Lag2 (DSL) Domain - EGF-like repeats - Transmembrane Domain - This segment anchors the ligand to the cell membrane. - Intracellular Domain (NICD) - While ligands do have an intracellular domain, its role is less understood than that of the Notch intracellular domain. However, it may help in signaling once the ligand binds to the receptor. OVERVIEW OF THE NOTCH SIGNALING PATHWAYA diagram of a cell Description automatically generated Notch Signaling Pathway is a chain reaction: - A ligand binds to notch, - This causes two cuts in notch, - The released NICD travels to the nucleus, - NICD activates certain genes, ultimately influencing cell function and development. Normally, Notch signaling keeps things balanced and makes sure cells only grow and divide as needed. But when Notch signaling becomes abnormal or "overactive", it can lead to diseases, including cancers. NOTCH SIGNALING IN DISEASES **Disease Type** **Key NOTCH Components ** **Affected Organs/Tissue** -------------------------------------------------------------------------------------------------------- --------------------------- ------------------------------ *CADASIL* (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) NOTCH3 Arterioles of the brain *Alagille Syndrome* NOTCH2 Liver, Heart, & other organs NOTCH SIGNALING IN CANCERS **Cancer Type** **Involved NOTCH Components** --------------------- ------------------------------- *Leukemia* NOTCH1, NOTCH2, NOTCH3 *Breast Cancer* NOTCH1, NOTCH3 *Colorectal Cancer* NOTCH1, NOTCH2 POTENTIAL THERAPEUTICS  - Therapies targeting Notch signaling aim to treat diseases, especially cancers and genetic disorders, where Notch signaling is overactive. - Gamma-Secretase Inhibitors (GSIs) - GSIs block an enzyme called gamma-secretase, which is needed to activate the Notch pathway. By blocking it, they stop Notch signaling, which can slow down cancer growth. - Monoclonal Antibodies - These are lab-made proteins that attach to either Notch receptors or the ligands that activate them, blocking the pathway. - Notch Decoys - These are \"fake receptors\" that bind to Notch ligands, preventing them from activating the real receptors. - Small Molecule Inhibitors & Peptides - Small molecules or peptides can block specific parts of the Notch pathway, preventing it from being fully activated. IMPORTANCE OF NOTCH SIGNALING  - Cell Differentiation - Notch signaling helps cells decide what specific role they will take on in the body, a process called differentiation. - Development - During development, Notch signaling is active in many organs and tissues, guiding cells to form organized structures. - Tissue Homeostasis - In adults, Notch signaling helps maintain the balance (homeostasis) of cells within tissues. - Cell Fate Decisions during Development - Notch signaling guides various cell fate decisions by telling cells whether to remain as stem cells (which can develop into different cell types) or to differentiate into a specific cell type. - Stem Cell Maintenance - Notch signaling plays a critical role in keeping certain cells in a stem cell state. By maintaining a pool of stem cells, tissues can continue to grow, repair, and regenerate.