Cell Signaling 2024 PDF

Cell Signalling T.S Wilkinson 21st October 2024  A few questions to start….. How much ‘cell signalling’ do you know? Did you study it for A-level? Where are you from? Wales, UK, International? Have you taken a break from education and are coming back? Gen/Bio, AMS..? Did or...

Cell Signalling T.S Wilkinson 21st October 2024  A few questions to start….. How much ‘cell signalling’ do you know? Did you study it for A-level? Where are you from? Wales, UK, International? Have you taken a break from education and are coming back? Gen/Bio, AMS..? Did or didn’t do Foundation year? Why did I ask these questions?  Learning objectives How cells communicate? Introduce different forms of communication Understand some of the molecules involved Understand some of the receptors involved Understand some of the cascades involved Chapter 15 MBC, p813-888  Type of communication Intercellular – Outside cells and between cells Intracellular – Inside cells, often from the cell surface to the nucleus or between organelles  Intercellular Communication between cells The are 4 forms – Contact dependent – Paracrine (and autocrine) – Synaptic – Endocrine Act over a long or short distance Messengers are called GROWTH FACTORS, CYTOKINES, HORMONES Intercellular  Intracellular SIGNAL in: Extracellular signalling molecule Receptor protein Intracellular signalling proteins Effector proteins SIGNAL out Intracellular signal transduction Cell surface receptor Transmembrane domains Adapter molecules Signalling molecules Nuclear localisation Gene transcription Intracellula r Cell signalling-how fast to a response? Cell movement Cell growth Cell secretion Cell metabolism Cell division Common effects on cells  Feedback loops Output feeds back to affect the same process Positive-output stimulates own production Negative-output inhibits its own production  Receptor proteins and complexes Ion channel receptors G-protein coupled receptors Enzyme coupled receptors Ion-channel coupled receptor Acetylcholine, Ca2+ and skeletal muscle contraction  Switch proteins help in cell signalling GTP-binding proteins Two types: Large – Trimeric G-protein coupled receptors Small (later in Level 2 and 3) – Monomeric GTPases – Controlled by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) – (e.g. Ras - a role on cancer biology)  G-protein coupled receptors 7 trans-membrane LARGE spanning receptor GTP-binding protein 3 sub-units Alpha, beta, gamma Switching during intracellular signalling GTP-binding proteins Cycle between ‘on’ and ‘off’ state GTP is ‘on’ but GDP is ‘off’  Nucleotide s Carry chemical energy in easily hydrolyzable forms Combine with other groups to form co- enzymes Used as specific signalling molecules in the cell  G-protein coupled receptor Largest family of cell surface receptors Cytosolic domain associates with G-proteins Variety of inactive proteins in the cytosol Receptor, trimeric G protein, other enzymes  G-proteins activate membrane bound enzymes Two major target enzymes for G proteins Adenylate Cyclase generates the small intracellular signalling molecule cyclic AMP Phospholipase C generates the small intracellular signalling molecules inositol triphosphate and diacylglycerol Adenylate cyclase Adenylate Cyclase generates the small intracellular signalling molecule cyclic AMP from ATP cAMP is degraded by cyclic AMP phosphodiesterase  Phospholipase C Phosphatidylinositol 4,5- bisphosphate or PtdIns(4,5)P2 , also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes Phospholipase C (PLC) generates the small intracellular signalling molecules inositol 1, 4, 5-triphosphate (IP3) and diacylglycerol (DAG)  PLC activates two pathways IP3 triggers Ca2+ release from ER DAG remains in the cell membrance and activates protein kinase C (PKC)  Enzyme coupled receptor Cytosolic domain has intrinsic enzyme activity One transmembrane domain Receptor dimerisation Switching also important with enzyme receptors Phosphorylation and de- phosphorylation Phosphorylate with a ‘kinase’ Dephosphorylate with a ‘phosphatase’  Receptor-associated complexes Ligand binds Conserved domains – Short peptide sequence – Covalent modification-phosphorylation Small interaction domains Like LEGO® bricks! Receptor activation-dimerization  Signalling pathways involve multiple proteins Depend on the receptor Use molecular switches throughout Often signal to an organelle and or the nucleus Result in gene changes or release of stored mediators – G-protein pathways – Receptor kinase pathways  Enzyme receptor coupled pathways Phospholipase C Phosphinositide-3-kinase (PI-3-kinase) Monomeric GTPases Janus kinases  G-protein cascade GPCR G-proteins cAMP Cyclic AMP dependent protein kinase (PKA) Signalling cascades..... JAK-STAT pathway Important later on Immunology Cytokines are the intercellular signalling molecules in immunology and inflammation  Summary to cell signalling Intercellular and Intracellular Ion channels, G-proteins and Enzyme linked receptors Phosphorylation and dephosphorylation as molecular switches Kinase adds a phosphate and Phosphatase takes it away Good summary reference: th