Signal Transduction

Signal Transduction - Chapter 19 Chapter 19 Signal Transduction Signal transduction • Intercellular signal transduction transduction –

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Unformatted text preview: Chapter 19 Chapter 19 Signal Transduction Signal transduction • Intercellular signal transduction transduction – Endocrine signaling: Chemical messengers (hormones) – Neuronal signaling: Electrochemical impulses Electrochemical impulses • Intracellular signal transduction transduction Hormones • • • Endocrine hormones act on cells distant from the site of their release Paracrine hormones (local mediators) act only on cells close to the cell that released them Autocrine hormones act on the same cell that release them Two general mechanisms of hormone actions Classes of hormones The major endocrine glands Neuroendocrine origins of hormone signals (adenohypophysis) (neurohypophysis) Major endocrine systems and their target tissues Cascade of hormone release Hypothalamic hormones (releasing factors) • • • Corticotropin-releasing factor (CRF) causes the anterior pituitary (adenohypophsis) to release adrenocorticotropic hormone (ACTH), which stimulates the release of adrenocortical steroids Thyrotropin-releasing factor (TRF) stimulates the anterior pituitary to release thyrotropin (thyroid-stimulating hormone; TSH), which stimulates the thyroid to synthesize and release T3 and T4 Gonadotropin-releasing factor (GnRF) stimulates the anterior factor (GnRF) the anterior pituitary to release luteinizing hormone (LH) and folliclestimulating hormone (FSH) → In males, LH stimulates the testes to secrete androgens; FSH promotes spermatogenesis spermatogenesis → In females, FSH stimulates the development of ovarian follicles; LH triggers ovulation • Growth hormone-releasing factor (GRF) and somatostatin (growth hormone release-inhibiting factor; GRIF) stimulate/inhibit GRIF) the release of growth hormone (GH) from anterior pituitary → GH (or somatotropin) directly accelerates the growth of a variety of tissues and induces the liver to synthesize somatomedins that stimulate cartilage growth and have insulinlike activities til Hormones from the posterior pituitary (neurohypophysis) poste • • Vasopressin (antidiuretic hormone; ADH) increases blood pressure and stimulates the kidneys to retain water Oxytocin causes contraction of uterine smooth muscle and th thereby induces labor Growth hormone and its receptor • • The ligand-induced dimerization of human growth hormone receptor brings together the receptor brings together the receptor’s intracellular domains in a way that activates an effector protein such as a tyrosine kinase Abnormal GH production causes abnormal growth hGH – GH overproduction → gigantism (before the growth plate is ossified) (before the growth plate is ossified) or acromegaly (after the growth plate is ossified only soft tissues grow without the skeletal growth) – GH deficiency → dwarfism Extracellular domain of hGH receptor hGH receptor Pancreatic islet hormones • • • The α cells secrete glucagon in response to low blood glucose levels The β cells secrete insulin in response to high blood glucose levels The δ cells secrete somatostatin to inhibit the release of insulin and glucagon Islets of Langerhans Gastrointestinal hormones • Gastrin – Produced by the gastric mucosa – Stimulates the secretion of HCl and pepsinogen the secretion of HCl and pepsinogen • • • Secretin – Produced by the mucosa of the duodenum (upper small intestine) in response to acidification by gastric HCl – Stimulates the pancreatic secretion of HCO3- so as to neutralize the acid th HCO th Cholecystokinin (CCK) – Produced by the duodenum in response to the products of lipid and protein digestion – Stimulates gallbladder emptying, the pancreatic secretion of digestive enzymes and HCO3- Gastric inhibitory peptide (GIP) or glucose-dependent insulinotropic polypeptide polypeptide – Produced by specialized cells lining the small intestine – Inhibits gastric acid secretion, gastric mobility, and gastric emptying – Stimulates pancreatic insulin release Thyroid hormones • • • • • • The thyroid gland produces triiodothyronine (T3) and throxine (T4) that stimulate metabolism in most tissues T3 and T4 are transported in complex with are transported in complex with plasma carrier proteins such as thyroxinebinding globin, prealbumin and albumin The binding of T3, and to as lesser extent T4, activates thyroid hormone receptor as a transcription factor in the nucleus, th resulting in increased rate of expression of numerous metabolic enzymes Hypothyroidism is characterized by lethargy, obesity, and cold dry skin, gy, whereas hyperthyrodism has the opposite effects Hypothyroidism during the fetal and immediate postnatal periods results in irreversible physical and mental irreversible physical and mental retardation, a syndrome named cretinism Iodine deficiency commonly leads to thyroid gland problems, specifically endemic goiter Biosynthesis of T3 and T4 in the thyroid gland Control of calcium metabolism • The biological functions of Ca2+ include: – Formation of hydroxyapatite, Ca5(PO4)3OH, the major mineral constituent of bone – Second messenger – Muscle contraction – Transmission of nerve impulses – Blood clotting clotting • Ca2+ homeostasis is maintained by three hormones – Parathyroid hormone (PTH) • Peptide hormone produced by the parathyroid gland • Increases serum [Ca2+] by stimulating its resorption from bone and kidney and by increasing the dietary absorption of Ca2+ from the intestine – Vitamin D • Increases serum [Ca2+] in a synergy with PTH – Calcitonin • Peptide hormone produced by the specialized thyroid gland cells • Decreases serum [Ca2+] by inhibiting the resorption of Ca2+ from bone and kidney Hormonal control of Ca2+ metabolism Vitamin D Inactive Enzymatic hydroxylation This active form promotes the intestinal absorption of dietary Ca2+, thereby increases serum [Ca2+]. Epinephrine and norepinephrine • Produced by adrenal medulla (core) under control of the (core) under control of the sympathetic nervous system • Bind to adrenergic receptors (α- and β-adrenoreceptors) on target cells • Mobilization of energy of energy resources and their shunting to where they are most needed (adrenaline) (noradrenaline) Steroid hormones • Adrenocortical steroids are produced by the adrenal cortex (outer layer) – The glucocorticoids affect carbohydrate, protein, and lipid li metabolism in a manner nearly opposite to that of insulin and influence a wide variety of other functions, including inflammatory reactions and the stress responses; e.g. cortisol, corticosterone ti – The mineralocorticoids regulate the excretion of salt and water by the kidney; e.g. aldosterone – The androgens and estrogens affect sexual development and androgens estrogens sexual development and function • Gonadal steroids are produced by the gonads – The androgens (male sex hormones) from testes in males; e.g. testosterone – The estrogens (female sex hormones) from ovaries in females; e.g. β-estradiol, progesterone Structures of steroid hormones Cortisol (Hydrocortisone) Corticosterone Glucocorticoids Testosterone Aldosterone Mineralocorticoid β-Esterdiol Gonadal steroids Progesterone Opioid peptidides • Polypeptide hormones secreted by anterior pituitary (adenohypophysis) that have opiatelike pituitary (adenohypophysis) that have opiatelike effects on the central nervous system – β-Endorphine (endogeneous morphine) – Methionine-enkephanlin (Tyr-Gly-Gly-Phe-Met) Met – Leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu) • Bind to opiate receptors in the brain • Important in the control of pain and emotional states • “Runner’s high” and acupuncture Nitric oxide • • • • Regulation of blood vessel dilation (vasodilator) Mediates the effect of antianginal organic nitrate drugs such as nitroglycerin Synthesized from arginine by NO synthase (NOS) Three isozymes of NOS – – – • • • • • • Neuronal NOS (nNOS, NOS-1) Inducible NOS (iNOS, NOS-2) Endothelial NOS (eNOS, NOS-3) The target of NO in smooth muscle cells is guanylate cyclase (GC), which catalyzes the conversion of GTP to the conversion of GTP to 3’,5’-cyclic GMP (cGMP), an intracellular second messenger GMP (cGMP) an intracellular second messenger that resembles cAMP. NO can rapidly diffuses across cell membrane and react with GC’s heme prosthetic group to yield nitrosoheme, whose presence increases GC’s activity by up to 200 fold. cGMP causes smooth muscle relaxation through its stimulation of protein phosphorylation by cGMP-dependent protein kinase. eNOS and nNOS but not iNOS are regulated by [Ca2+]. The effects of increased cGMP synthesis diminish after the stimulus ceases, because a specific phosphodiesterase (cGMP PDE) converts cGMP to the inactive 5'-GMP. Inhibition of cGMP PDE causes cGMP levels to remain elevated once raised by an Inhibition of cGMP PDE causes cGMP levels to remain elevated once raised by an appropriate stimulus (e.g. sildenafil is an inhibitor of cGMP PDE). Four features of signal-transducing systems Six general types of receptors • • • • • • Gated ion channels open and close in response to the binding of chemical ligands or changes in transmembrane potential (e.g. Ach receptor) Receptor enzymes catalyze the production of an intracellular second messenger when activated by their extracelluar ligands (e.g. insulin receptor) Receptor proteins (serpentine receptors) indirectly activate (through GTP-binding proteins, or G proteins) enzymes that generate intracellular second messengers (e.g. β-adrenergic receptor system) Nuclear receptors (steroid receptors) alter the rate at which specific genes are transcribed and translated into cellular proteins Receptors with no intric enzymatic activity attract and activate cytoplasmic enzymes that act on downstream proteins, either by directly th di converting them to gene-regulating proteins (e.g. JAK-STAT system) or by activating a cascade of enzymes that finally activates a gene regulator (e.g. Toll signaling system) Adhesion receptors interact with macromolecular components of the receptors with macromolecular components of the extracellular matrix (such as collagen) and convey to the cytoskeletal system instructions on cell migration or adherence to the matrix (e.g. integrins) Six general types of signal transducers Ion channels underlies electrical signaling in excitable cells ce Ligand-gated ion channel Acetylcholine receptor ion channel Gated ion channels in neural transmission G protein-coupled receptors (GPCRs) • • • • A.k.a. serpentine receptors or 7 transmembrane segment (7TM) receptors The receptor with seven transmembrane α-helices is coupled through guanosine nucleotide-binding protein (G protein) to an enzyme in the plasma membrane that generates an intracellular second that generates an intracellular second messenger By alternating between two discrete conformations, one with ligand bound and one without the receptor can and one without, the receptor can transmit an extracellular signal to the cell interior The human genome encodes more than 1,000 members of GPCRs, specialized for transducing messages as diverse as light, smells, tastes, and hormones retinal X-ray structure of bovine rhodopsin Heterotrimeric G proteins • • • α Subunit (Gα) • Binds to GTP or GDP • GTPase activity (GTP → GDP + Pi) at the relatively sluggish rate • Anchored to the membrane by a myristoyl or palmitoyl group, or both to the membrane by myristoyl or palmitoyl group or both β Subunit (Gβ) γ Subunit (Gγ) • Anchored to the membrane by prenylation • Very tight binding to Gβ to form Gβγ GDP Activation and self-inactivation of G proteins Binding of Gα⋅GDP-Gβγ (unactivated state) to GPCR in complex with ligand Induction of Gα to exchange its bound GDP for GTP Conformational changes in three switch regions of Gα cause Gα to dissociate from Gβγ Gα⋅GTP (activated state) + Gβγ (activated state) (activated state) state) GTP hydrolysis in Gα by its GTPase activity causes hydrolysis in its GTPase activity causes the G protein to reassemble as the inactive G⋅GDP-Gβγ complex G protein activation and self-inactivation G proteins activate other proteins • Adenylate cyclase – activated by a stimulatory G protein, Gsα activated by stimulatory protein – inhibited by an inhibitory G proteins, Giα • • • • Ion channels channels Phosphoinositide signaling system Phosphodiesterases Protein kinases The adenylate cyclase signaling system Drugs that affects the adenylate cyclase signaling th th (an asthma treatment) (an ingredient of chocolate) Antagonists of adenosine receptors that act through inhibitory G proteins → an increase in cAMP concentration leads to stimulation Toxins that affects the adenylate cyclase signaling • • • Cholera toxin (secreted by Vibrio cholerae) causes cholera. Vib – Upon entry into cells, it’s A subunit catalyzes the transfer of the ADP-ribose unit from NAD+ to a specific Arg side chain of Gsα, whose GTPase activity is therefore blocked. – ADP-ribosylated Gsα continuously activates adenylate cyclase and consequently Gs activates adenylate cyclase and consequently cellular cAMP levels increase ~ 100 fold. – Secretion of enormous amount of digestive fluids (an HCO3--rich salt solution) in response to the elevated cAMP level. Heat-labile enterotoxin (secreted by pathogenic E. coli) causes a diarrheal disease similar to but less serious than cholera disease similar to but less serious than cholera. Pertussis toxin (secreted by Bordetella pertussis) causes pertussis or whooping cough. – ADP ribosylation of a specific Cys residue of Giα – The modified Giα cannot exchange its bound GDP for GTP and therefore cannot inhibit adenylate cyclase inhibit adenylate cyclase Receptor tyrosine kinases (RTKs) • A single transmembrane segment • Usually monomer in the unligated state (the insulin receptor is unusual in that it is a dimer in the unligated state) • The most common activation mechanism is the ligandmost common activation mechanism is the ligand induced dimerization (or the conformational changes on insulin binding, in the case of the insulin receptor), which leads to the cross leads to the cross-phosphorylation each other on specific each other on specific tyrosine residues • Growth factor receptors – Epidermal growth factor receptor (EGFR) (EGFR) – Platelet-derived growth factor receptor (PDGFR) – Fibroblast growth factor receptor (FGF) Domain organization in a variety of receptor ty tyrosine kinase subfamilies sub Schematic diagrams of RTKs Autophosphorylation of the insulin-receptor Tyr kinase Regulation of gene expression by insulin Binding modules to relay the signal • • • • • • SH2 (Src homology domain 2) domains specifically bind phosphoTyr residues in their target peptides with high affinity PTB (Phosphotyrosine-binding) domains also bind phosphoTyrcontaining peptides (NPXpY) SH3 domains bind to proline-rich peptide WW domains bind to proline-rich sequence PH (Pleckstrin homology) domains bind to the inositol head groups of phosphoinositides phosphoinositides PDZ domains bind to the C-terminal tripeptide, Ser/Thr-X-Val, of its target proteins Phospho-Tyr SH2 domain Some binding modules of signaling proteins The Ras signaling pathway • Ras (or c-Ras), a proto-oncogene product, is a monomeric membrane-anchored (by prenylation) G protein which is activated by phosphorylated RTKs via protein, which is activated by phosphorylated RTKs via a Grb2-Sos complex and in turn activates a downstream “kinase cascade” • The signaling pathway downstream of Ras consists of a signaling pathway downstream of Ras consists of linear cascade of protein kinases – Raf, a Ser/Thr kinase is activated by Ras⋅GTP – MEK (MAP kinase/ERK kinase-activating kinase) or MAP kinase/ kinase MAP kinase kinase is phosphorylated and thus activated by Raf – Mitogen-activated protein kinases (MAPKs) or extracellularsignal-regulated kinases (ERKs) is phosphorylated at both its Thr and Tyr residues by MEK and thereby activated Thr and Tyr residues by MEK and thereby activated – The activated MAP kinases migrate from the cytosol to the nucleus, where they phosphorylate a variety of transcription factors, including Fos, Jun, and Myc The Ras-activated MAP kinase cascade MAP kinase cascades in mammalian cells Tyrosine Kinase-Associated Receptors • Many receptors for growth hormone, the cytokines, the interferons, and T cell receptors • Ligand binding induces these receptors to dimerize (or trimerize) to activate associated nonreceptor tyrosine kinases (NRTKs) (e.g. Jak, Src etc) The JAK-STAT pathway • Ligand binding induces the cytokine receptor to dimerize • The Janus kinase (JAK) family of NRTKs in complex with th the receptor phosphorylate each other and then their th th associated receptors • STATs (Signal Transducers and Activators of Transcription) bind to the phosphoTyr group on their bind to the phosphoT gro on their cognate activated receptor via their SH2 domain and are then phosphorylated on a conserved Tyr residue by the associated JAK associated JAK • Upon their dissociation from the receptor, the phosphorylated STATs homo- or heterodimerize via the association of their phosphoTyr residue with the SH2 association of their phosphoTyr residue with the SH2 domain on the opposing subunit • The STAT dimers are then translocated to the nucleus and act as transcription factors by themselves and act as transcription factors by themselves The JAK-STAT pathway Autoinhibition of Src Tyr kinase Protein tyrosine kinases are targets of anticancer drugs ta Imatinib (Gleevec) Treatments of chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies The Abl PTK domain in complex Abl PTK domain in complex with a truncated derivative of gleevec Protein phosphatases turn off signals by dephosphorylation dephosphorylation • Protein tyrosine phosphatases (PTPs) also mediate signal transduction – Receptorlike PTPs – Intracellular PTPs PTP – Dual-specificity PTPs, which can also dephosphorylate phospho dephosphorylate phospho-Ser/Thr residues residues • Protein Ser/Thr phosphatases – PPP family: PP1, PP2A, and PP2B (calcineurin) family: PP1, PP2A, and PP2B (calcineurin) – PPM family: PP2C Calcineurin is the target of immunosuppressant drugs • • • Calcineurin plays an essential role in the antigen in the antigen-induced proliferation proliferation of T cells Cyclosporin A (CsA) and FK506 are highly effective immunosuppressants that are in clinical use for the prevention of organ-transplant rejection and for the treatment of autoimmune the treatment of autoimmune disorders The drug-immunophilin complexes (CsA⋅Cyclophilin and FK506⋅FKBP) can bind to and inhibit calcineurin CaN B subunit CaN A subunit FK506 FK506 FKBP Cyclosporin A FK506 (Tacrolimus or fujimycin) The phosphoinositide cascade • The plasma membrane phospholipase C (PLC) that is activated through GPCR hydrolyzes the plasma membrane lipid phosphatidylinositol 4,5bisphosphate (PIP2) to two second messengers – diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) • IP3 bind to the specific receptors on the endoplasmic reticulum and open Ca2+ channels within the ER to release Ca2+ to cytosol • Ca2+ is also a second messenger in many signal transduction transduction • DAG cooperates with Ca2+ in activating protein kinase C (PKC), a Ser/Thr protein kinase Molecular formula of the phosphatidylinositides The specificity of phospholipases PIP2 is hydrolyzed to two second messengers The phosphoinositide cascade Phorbol esters stimulate PKC • Phorbol esters are potent activators of protein kinase C; they structurally resemble DAG but bind to PKC with ~ 250 250-fold greater affinity greater affinity • Consequently, phorbol esters are the most effective tumor promoters (substances that are not in themselves carcinogenic but increase the carcinogenic but increase the potency of known carcinogens) X-ray structure of the C1B motif of PKC in complex with phorbol-13-acetatate Phosphoinositide kinases • The inositol head group of phosphatidylinositol is phosphoryated at its its 3-, 4-, and 5-positions by the and by the corresponding phosphoinositide kinases – Phosphoinositide 3-kinases (PI3Ks) – Phosphoinositide 4-kinases (PIP4Ks) – Phosphoinositide 5-kinases (PIP5Ks) • • The various phosphoinositides function as second messengers by recruiting the proteins that bind them to the cytoplasmic th bi th th surface of the plasma membrane The resulting colocalization of enzymes and substrates results in further signaling and substrates results in further signaling activity for many cellular functions such as cell survival, proliferation, cytoskeletal rearrangement, and vesicle trafficking Inositol polyphosphate phosphatases Signaling via the phosphoinositide cascade is terminated through the actions of a variety of inositol phosphatases (1, 3-, 4-, and 5-phosphatases) – Inositol polyphosphate 5-phosphatases terminate the actions of Ins Ins-1,4,5-P3 and Ins-1,3,4,5-P4 actions in numerous signaling Ins in numerous signaling pathways – Inositol polyphosphate 1-phosphatase hydrolyzes Ins-1,4-P2 and Ins Ins-1,3,4-P3 and is inhibited by Li+ ion, which is used for treating is inhibited by Li which is used for treating bipolar disorders – Inositol polyphosphate 3-phosphatases undo the actions of the PI3Ks One of these class enzymes PTEN is tumor suppressor PI3Ks. One of these class enzymes PTEN is a tumor suppressor (a protein whose loss of function results in cancer) – Inositol polyphosphate 4-phosphatases hydrolyze Ins-1,3,4-P3, Ins Ins-2,4-P2, and PtdIns-3,4-P2 and PtdIns Regulation of transcription by steroid and thyroid hormones, retinoids, and vitamin D Hormone receptors Drugs that controls steroid hormonal signaling • Estrogen receptor antagonist • Blocks the hormonal action of estrogen whose continuous estrogen whose continuous presence is required for the division of some types of breast cancer cells • Progesterone receptor antagonist • Blocks the hormonal action of progesterone which is essential to progesterone, which is essential to implantation of the fertilized ovum in the uterus Four stages of the cell cycle Regulation of the cell cycle by protein kinases • • • • • • The timing of the cell cycle is controlled by a family of protein kinases The kinases are heterodimers kinases are heterodimers with a regulatory subunit, cyclin, and a catalytic subunit, cyclindependent protein kinase (CDK) Animal cells have at least 10 different cyclins and at least 8 CDKs, which act in various combinations at specific points in the cell cycle the cell cycle When cyclin binds, the catalytic site of CDK opens up, and the activity of the catalytic subunit increases 10 increases 10,000-fold Phoshorylation of a Thr residue holds CDK in its active conformation CDKs regulate cell division by regulate cell division by phosphorylating their target proteins ATP Cyclin CDK CDK (inactive) Phospho-CDK Levels of CDK activities oscillate Four mechanisms for regulating CDK activity – – – – Phosphorylation and dephosphorylation of the CDK Controlled degradation of cyclins Regulated synthesis of CDKs and cyclins Specific CDK-inhibiting proteins (e.g. p21) Regulation of CDK by by phosphorylation and proteolysis DBRP (destruction box recognizing protein) Regulation of cell division by growth factors Some important target proteins of CDKs • • • Laminin – The structure of the nuclear envelope is maintained in part by highly organized meshworks of intermediate filaments composed of the protein laminin laminin. – The phosphorylation of laminine by CDK causes laminin filaments to depolymerize Myosin – ATP-driven actin-myosin contractile machinery pinches a dividing cell actin contractile machinery pinches dividing cell into two equal parts during cytokinesis – After cell division, CDK phosphorylates a small regulatory subunit of myosin, causing dissociation of myosin from actin filaments and inactivating the contractile machinery inactivating the contractile machinery Retinoblastoma protein (pRb) – The unphosphorylated pRb binds the transcription factor E2F, blocking the transcription of a group of genes necessary for DNA synthesis (cell cycle is arrested in G1) The phosphorylation of pRb by cyclin cycle is arrested in G1). The phosphorylation of pRb by cyclin E-CDK2 relieves this blocking mechanism – When DNA damage is detected, p53 is activated and serves as a transcription factor that stimulates the synthesis of the protein p21. This protein inhibits the cyclin protein inhibits the cyclin E-CDK2 and causes pRb-E2F complex to and causes pRb complex to arrest the cell cycle in G1 Regulation of passage from G1 to S Cancer • • Uncontrolled proliferation of cells Two types of tumors – Benign tumors grow by simple expansion and remain encapsulated by a layer of connective tissue ti – Malignant tumors (cancers) grow in an invasive manner and colonize new sites in the body (metastasis) • • • • • Cancer is caused by carcinogens, radiation, and viruses Almost all malignant tumors result from the transformation of a single cell (conversion to the cancerous state) Transformation requires a cell or its ancestors to have undergone several independent and presumably improbable carcinogenic several independent and presumably improbable carcinogenic changes Oncogenes are genetically dominant and may encode defective growth factors, receptors, G proteins, protein kinases, or transcription factors transcription factors Tumor suppressor genes encode regulatory proteins that normally inhibit cell division; mutations in these genes are genetically recessive but can lead to tumor formation Oncogenes and cancer • • • • • v-src (v for viral, src or sarcoma) oncogene – Oncogene from Rous sarcoma virus (RSV), which induces the formation of sarcomas (cancer arising from connective tissues) in chickens – Uninfected chicken cells contain c-src (c for cellular) that is homologous to v-src and that is highly conserved in wide variety of eukaryotes and that is highly conserved in a wide variety of eukaryotes – Both v-src and c-src encode a tyrosine kinase – Uncontrolled v-src leads to a cancer v-erbB oncogene – Encodes a truncated version of the epidermal growth factor (EGF) receptor, which truncated version of the epidermal growth factor (EGF) receptor which lacks the EGF-binding domain but retains its transmembrane segment and its tyrosine kinase domain – Phosphorylation of its target proteins in the absence of an extracelluar signal drives uncontrolled cell proliferation v-ras oncogene – Encode v-Ras protein, that resembles cellular Ras (c-Ras) but hydrolyzes GTP much more slowly – The reduced braking effect of GTP hydrolysis leads to the increased activation of the kinases downstream of Ras the kinases downstream of Ras v-fos and v-jun oncogenes – Encode proteins that are nearly identical to their cellular counterparts (fos and jun) and mimic their effects as transcription factors on host cells but in an uncontrolled manner Proto-oncogenes, the normal cellular analogs of oncogenes could be mutated to form oncogenes Oncogene-encoded defective EGF receptor Conversion of a regulatory gene to to a viral oncogene Defects in tumor suppressor genes lead to cancer • Unlike oncogenes which are genetically dominant, the tumor suppressor genes are genetically recessive • Mutations in both copies of the tumor suppressor genes in chromosomes lead to the unregulated growth of cells – Retinoblastoma, a cancer of the retina results from mutations in the gene for pRb – In more than 90% of skin cancer and about 50% of all more than 90% of skin cancer and about 50% of all other human cancers, p53 is defective • Cancer is generally the result of an accumulation of mutations (sometimes over several decades) in tumor suppressor genes and/or proto-oncogenes Programmed cell death (Apoptosis) • Cell death is programmed in many cellular processes – Some cells must die during development – Cells that produce anti-self antibodies must die that produce anti antibodies must die – Menstruation • • • • Apoptosis is also induced by other cellular stresses such as virusinfection, heat, hyperosmolarity, UV light, and γ irradiation The regulatory mechanisms that trigger apoptosis involve some of the same proteins that regulate the cell cycle Apoptosis can be triggered by extracellular signals such as tumor necrosis factor (TNF) and Fas ligand through their corresponding necrosis factor (TNF) and Fas ligand through their corresponding plasma membrane receptors → The activated receptors (TNF-R and Fas) foster interaction between the “death domain” in the receptors themselves and the death domain in their cytosolic target proteins such as TRADD and FADD, which in turn activate a family of as tu act calcium-dependent cysteine proteases (caspases) The activated caspases triggers a series of proteolytic events, which eventually lead to the cell death Initial events of apoptosis Sensory transduction in vision, olfaction, and gustation gustat • • • • Specific serpentine receptors stimulate their corresponding heterotrimeric G proteins The activated G proteins activate effector enzymes Changes in concentration of the second messengers result in alterations in the permeability of ion channels The resulting depolarization or hyperpolarization lead to the change the Vm of the sensory th th neuron, which is passed through relay neurons to sensory centers in the brain sensory centers in the brain Light reception in the vertebrate eye (more sensitive to light but cannot discriminate colors) (less sensitive to light but discriminate colors) Mechanism of visual signal transduction • • • In rod and cone cells of the retina, light activates rhodopsin which stimulates rhodopsin, which stimulates replacement of GDP by GTP on the G protein transducin The freed α-subunit of transducin activates cGMP phosphodiesterase, which lower [cGMP] and thus closes cGMP cGMP-dependent ion channels ion channels in the outer segment of the neuron The resulting hyperpolarization of the rod or cone cells carries the signal to the next neuron in the pathway, and eventually to the brain the brain Molecular events of vision Vertebrate olfactory system • In olfactory neurons, olfactory stimuli acting olfactory stimuli, acting through serpentine receptors and G proteins (Golf), trigger either an increase in [cAMP] (by activating adenylyl cyclase) or an increase in [Ca2+] (by activating PLC). • These second messengers Th affect ion channels and thus the Vm Molecular events of olfaction Vertebrate gustatory system • • • • • • The sense of taste in vertebrates reflects the activity of gustatory neurons clustered in taste buds on the surface of the tongue the tongue When the sweet tasting molecule binds, the serpentine receptor in sweet taste buds stimulates the replacement of GDP by GTP on the heterotrimeric G protein gustducin gustducin The activated gustducin stimulates cAMP production by adenylyl cyclase The resulting elevation of [cAMP] activates PKA, which phosphorylates K+ channels in the plasma membrane, causing them to close The resulting depolarization carries the signal to the next neuron in the pathway, and eventually to the brain and eventually to the brain Other taste buds specialized in detecting bitter, sour, or salty tastants, use various combinations of second messengers and ion channels in the transduction mechansms mechansms Transduction mechanism for sweet tastants ...
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This note was uploaded on 10/16/2010 for the course CHEM 60280 taught by Professor Ryu during the Spring '09 term at TCU.

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