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Transcript
CHAPTER 15 Cell Signaling and Signal Transduction: Communication Between Cells Signal transduction • Extracellular ligand: 1st messenger – Autocrine: ligand binds to producing cell – Paracrine: ligand binds to a neighbor cell – Endocrine: ligand binds to a distant cell after traveling through the circulatory system Signal transduction • Cells respond to a ligand only if expressing the cognate receptor – 1st messenger binds to receptor • Outside cell • Binds to cell surface – Effectors generate 2nd messengers • Inside cell • Signal amplification • Some diffuse through cytosol • Some diffuse within plasma membrane • Exert allosteric effects on various enzymes & proteins Signal transduction • Cells respond to a ligand only if expressing the cognate receptor – 1st messenger binds to receptor • Outside cell • Binds to cell surface • Alters receptor conformation – Signaling pathway • Each protein alters the conformation of next protein • Conformation usually altered by phosphorylation • Target proteins ultimately alter cell activity – E.g. TXN, TLN, Enzymes, etc • Signal amplification A Survey of Extracellular Messengers • Extracellular messengers (the signal) include: – Small molecules such as amino acids, steroids, lipids and their derivatives serotonin – Gases such as NO and CO – Various peptides and proteins Edn1 G protein-coupled receptors (GPCRs) BINDING – GPCRs involved in vision, smell, emotion (1000s of genes) – Respond to a wide variety of ligands • Proteins, small chemical compounds, metabolites, photons G protein-coupled receptors (GPCRs) BINDING – GPCRs involved in vision, smell, emotion (1000s of genes) – Respond to a wide variety of ligands • Proteins, small chemical compounds, metabolites, photons – Ligands bind to extracellular side of receptor • Induces a conformational change in intracellular domains – 7 transmembrane (7TM) domains • serpentine structure passed through membrane 7 times N 1 2 3 45 6 7 C GPCRs ACTIVATION / SIGNAL TRANSMISSION – Receptor is ‘coupled’ to a large heterotrimeric G protein “switch” • Alpha, beta and gamma subunits • Alpha subunit = GTP hydrolyzing enzyme (GTPase) • GTP bound form is switched ‘on’ • GDP bound form is switched ‘off’ • The ligand-bound receptor promotes exchange of GDP for GTP “off ” GTP G-GDP N GDP Active receptor “on” G-GTP 1 2 3 45 6 7 C RGS G-GDP G-GTP Pi GPCRs ACTIVATION / SIGNAL TRANSMISSION – Four classes of G-alpha subunit – G-alpha-s increases activity of Adenylate Cyclase (AC) • An “Effector” • ATP --> cAMP + PPi • cAMP is a 2nd messenger generated within the cytoplasm – G-alpha-i decreases activity of AC ACTIVATION / SIGNAL TRANSMISSION – G-alpha-q increases activity of the effector Phospholipase C (PLC) • PI(4,5)P2 --> DAG + IP3 • DAG and IP3 are both 2nd messengers – G-alpha-12/13 is not well understood, but is linked to cancer GPCRs TERMINATION • Regulators of G protein Signaling (RGS) – Enhance GTPase activity • GPCR-kinases (GRKs) – Phosphorylate internal portions of active receptors • Arrestins – Compete with G-alpha for binding to phosphorylated GPCR • Desensitization: loss of response to a stimulus in spite of the continued presence of the stimulus Signal transduction • Epinephrine: glucose mobilization – G-alpha-s – Increased AC activity – Increased [cAMP] – cAMP allosterically activates Protein Kinase A (PKA) • PKA inhibits Glycogen Synthase • PKA activates Glycogen Phosphorylase – Leads to glycogen breakdown and release of glucose • PKA stimulates TXN factor activity – Phosphorylates cAMP Response Element Binding (CREB) protein – Drives TXN of various target genes GPCRs • G-alpha-q • Increased Phospholipase C (PLC)-beta activity – Hydrolyzes specific phospholipids – Increased [diacylglycerol (DAG)] and [inositol triphosphate (IP3)] • G-alpha-q • DAG allosterically activates Protein Kinase C (PKC) • IP3 allosterically opens a Calcium channel on the smooth Endoplasmic Retriculum – Increased [Ca2+] in cytoplasm • G-alpha-q • Increased [Ca2+] in cytoplasm – Ca2+ binds many cytoplasmic proteins – Calmodulin, regulator of many proteins • G-alpha-q • Increased [Ca2+] in cytoplasm – Ca2+ can pass through GAP junctions into neighboring cells – Ca2+ gated Ca2+ channels in neighboring cells open further increasing [Ca2+] – Propagation of Ca2+ effects through GAP junctions integrates tissue response (Ca2+ waves) Video Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes – Extracellular ligand binding domain • Ligand binding triggers receptor dimerization Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes – Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes – Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors • Phospho-Y (PY) sequences are binding sites for additional protein factors • SH2 domains in proteins such as Src and Grb2 bind to PY-receptor Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes – Intracellular tyrosine (Y) kinase domain • Dimerization allows for trans-autophosphorylation of the receptors • Phospho-Y (PY) sequences are binding sites for additional protein factors • SH2 domains in proteins such as Src and Grb2 bind to PY-receptor – Drag partner proteins along with them from the cytoplasm to the membrane Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes – The Ras - Mitogen Activated Protein Kinase (MAPK) pathway • Ras is a small G protein “switch” (single subunit, no beta or gamma) • Over 100 Ras family genes • Lipid anchor to plasma membrane • Disease: ~30% of cancers have activating Ras mutations (break the GTPase) “off ” GTP Ras-GDP GDP GEF GAP Ras-GDP Pi “on” Ras-GTP Ras-GTP Signal transduction • Receptor Tyrosine Kinases (RTKs): over 90 genes – The Ras - Mitogen Activated Protein Kinase (MAPK) pathway • Ras is a small G protein “switch” (single subunit, no beta or gamma) • GEF = Guanine Nucleotide Exchange Factor (e.g. Sos) • GAP = GTPase Activating Protein “off ” GTP Ras-GDP GDP GEF GAP Ras-GDP Pi “on” Ras-GTP Ras-GTP RTK: Insulin receptor Signal transduction • Convergence – ECM --> Integrin --> Ras – EGF --> EGFR --> Ras Signal transduction • Crosstalk – cAMP can block growth by inhibiting Raf