Chapter 15: Signal transduction

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1 Chapter 15: Signal transduction Know the terminology: Enzyme-linked receptor IP3+DAG G-protein linked receptor camp nuclear hormone receptor Ca 2+ G-protein adaptor protein protein kinase scaffolding protein SH2 domain MAPK Ras phosphodiesterase phospholipase protein phosphatase crosstalk

2 Chapter 15: Signal transduction Outline: General principles of signal transduction Overview of: Signaling Receptors Transducers Targets Major types of cell-surface receptors - RTK signaling - G-protein signaling

3 General Principles of Signal Transduction Communication usually involves (i) a signaling molecule, (ii) a receptor, (iii) intracellular signal transducers and (iv) targets

4 General Principles of Signal Transduction 2. Each cell responds to a complex profile of signaling molecules (crosstalk)

5 General Principles of Signal Transduction 3. Different cells respond differently to a particular signaling molecule

6 General Principles of Signal Transduction 4. Cells can remember the effects of some signals 5. Cells can adjust their sensitivity to a signal

7 General Principles of Signal Transduction 4. Cells can remember the effects of some signals 5. Cells can adjust their sensitivity to a signal

8 General Principles of Signal Transduction 6. Signal can exhibit complex responses to signal concentration

9 Signaling molecules Signaling molecules come in many chemical forms: Proteins: insulin, glucagon Steroids et al.: testosterone, estradiol, cortisol Amines: thyroxine, catecholamines, acetylcholine Gases: nitric oxide Signaling pathways require molecules with rapid rates of synthesis and degradation Typically released from one cell and recognized by another cell

10 Signaling molecules Secretory signals: Autocrine-signals affect same cell or cell type Paracrine-signals affect neighbouring cell Endocrine-signals affect distant cells Contact-dependent signals: -signals are not released but affect other cells in contact through protein-protein interactions

11 Autocrine signaling Signals released by one cell affect other cells in the immediate vicinity Amplify a response by inducing many like-cells to respond in the same way Allows cells to exhibit a coordinated response (a community effect)

12 Autocrine signaling

13 Paracrine signaling Signals released by one cell affect different cells in the immediate vicinity Synaptic transmission resembles paracrine stimulation but the response is limited to cells in very close proximity The outward propagation of the signal is limited by -cellular uptake, -extracellular degradation -& binding

14 Endocrine signaling Signals released by one cell affect different cells far away Endocrine signaling often exerts multiple effects on the organism by affecting many different tissues

15

16 Receptors = Proteins that bind signals and initiate a signaling cascade Cell membrane receptors -integral membrane proteins that bind an extracellular signal and start a signal cascade Intracellular receptors -nuclear hormone receptors

17 Nuclear hormone receptors Examples include -steroid hormone receptor and -thyroid hormone receptor -Retinoic acid receptor -Vitamine D receptor NHRs are transcription factors that respond to specific ligands Ligands alter the ability to bind to specific DNA regulatory elements

18 Intracellular signal transduction Once the receptor is activated, the signal is propagated by proteins that act as: Relay proteins Messenger proteins Adaptor proteins Amplifier proteins Transducer proteins Bifurcation proteins Integrator proteins Latent gene regulatory proteins

19

20 Intracellular signal transduction Activated cell membrane receptors can alter the activity of intracellular enzymes including: Protein modifying enzymes Kinases (PKA, PKC, PKG)/ phosphatases acetylases/ deacetylases Lipid modifying enzymes Phospholipases (PLCβ ou γ) Phosphotidyl inositol kinase (PI3K) Nucleotide modifying enzymes cyclases/ phosphodiesterases

21 Protein kinases

22 Phospholipases PLC generates DAG and phosphoinositides, such as IP3 (inositol 1, 4, 5- triphosphate)

23 Targets The final targets of signaling cascades are usually proteins: Regulators of gene expression (transcription factors, histone remodeling enzymes) Enzymes (metabolic enzymes) Structural proteins (cytoskeletal proteins) Effects alter activity (catalytic, DNA binding) or the ability to interact with other proteins (structural proteins, subcellular localization).

24 Cell surface receptors 3 main classes of cell surface receptors: Ion-channel linked receptors Enzyme linked receptors may possess intrinsic enzyme activity or once ligands bind, activate enzyme activity G-protein linked receptors are monomeric (7TM) and activate trimeric G-protein (GTP-binding protein) that regulate downstream proteins

25 Enzyme-linked receptors 5 main classes distinguished by: type of effector (e.g. kinase vs. phosphatase) target (serine/threonine, tyrosine, histidine) type of linkage between receptor and enzyme 1. Receptor tyrosine kinase (RTK) 2. Tyrosine kinase linked receptor 3. Receptor serine/threonine kinase (PKA, PKC, PKG, PK-Ca 2+ -CAM) 4. Receptor guanylyl cyclase 5. Histidine-kinase associated receptors

26 Receptor tyrosine kinases Most common type of receptor for many common protein hormones including EGF, PDGF, FGF, HGF, IGF-1, VEGF, NGF.

27 Receptor tyrosine kinases Receptor itself possesses intrinsic tyrosine kinase activity Once the ligand binds, the receptor can dimerize and it become an active tyrosine kinase It phosphorylates itself (autophosphorylation), causing: 1. Increase kinase activity 2. Increased affinity for other proteins Once bound, these docking proteins can become phosphorylated

28 Figure Domain organization in a variety of receptor tyrosine kinase (RTK) subfamilies. Page 684

29 Structure of the 2:2:2 complex of FGF2, the D2 D3 portion of FGFR1, and a heparin decasaccharide. D2 Heparin decasaccharide D3

30 Ligand-dependent autophosphorylation and docking

31 Ligand-dependent autophosphorylation and docking

32 Page 686 Schematic diagrams of RTKs.

33 Page 687 Structure of the PTK domain of the insulin receptor. PTK Domain undergoes major conformation change & autophosphorylation (1 to 3 Tyr residues)

34 Relaying the signal: Binding Modules, Adaptors, GEF, GAP SH2 domains mediate signal Transduction PTB domains bind py-containing peptides SH3 domains bind Pro-rich peptides SH2 P T B SH3 GRB2 P P P GEF

35 Structure of the 104-residue Src SH2 domain in complex with an 11- residue polypeptide containing the protein s pyeei target tetrapeptide. Page 691 Src homology (SH2): present in PTK, PLC-γ, certain GAP, etc SH2 domain bind specifically phosphotyr residues in target peptides with high affinity (hydrophobic pocket) recognizes sequence of target peptide on C-terminal side of py does not bind phospho-ser/phospho-thr (much more abundant) SH2 P T B SH3

36 PTB domain of Shc in complex with a 12-residue polypeptide from the Shc binding site of a nerve growth factor (NGF) receptor. Page 692 PTB domain: Specifically binds phospho-tyr target peptides Consensus domain NPXpY Recognizes the sequence on N-terminal side of py SH2 P T B SH3

37 SH3 domain from Abl protein in complex with its 10- residue target Pro-rich polypeptide (APTMPPPLPP). Page 693 SH3 domain: Molecular velcro: mediate interactions between kinases & regulatory proteins present in great variety of proteins receptor Tyrosine Kinases non-receptor Tyrosine Kinases, adaptor proteins (ex. Grb2) structural proteins (myosin, spectrin) bind Pro-rich peptides GF P SH2 GRB2 SH3 PSOS Ras P P

38 Relaying the signal: Binding Modules, Adaptors, GEF, GAP SH2 domains mediate signal Transduction PTB domains bind py-containing peptides SH3 domains bind Pro-rich peptides Other Binding Modules WW domain (2 Trp residues) Plekstrin homology domain (PH domain) PDZ domain Relay: Grb2, Shc & IRS: adaptor proteins recruit Sos to the vicinity of Ras Ras is activated by RTK via Grb2-SOS complex

39 Grb2. Complex between Ras and the GEF-containing region of Sos. Page 694 Relay: Grb2, Shc & IRS: adaptor proteins recruit Sos to the vicinity of Ras Ras is activated by RTK via Grb2-SOS complex Sos opens Ras s Nucleotide Binding Site GAP functions to turn Off Ras-mediated Signals

40 JUST THE TIP OF THE ICEBERG OF PROTEIN DOMAINS USED FOR PROTEIN/PROTEIN INTERACTIONS

41 Docking of intracellular proteins on phosphotyrosines Phosphotyrosine domains are binding sites for many different proteins with SH2 (=PTB) domains These can be enzymes (e.g., PLC, PI3K) or they can act as adaptor molecules to bind other proteins (e.g. Grb2)

42 Linking RTK to Ras and the MAPK cascade Once an adaptor protein binds to the RTK (e.g., Grb2), it attracts another protein - Ras GEF (guanine nucleotide exchange factor) Ras GEF induces Ras to exchange its GDP for GTP (activating Ras). Active Ras then activates MAPKKK, which phosphorylates and activates MAPKK, which phosphorylates and activates MAPK, which phosphorylates many proteins, including transcription factors.

43 Ras GTPase Cycle GTP Ras-GTP H 2 O Exchange Hydrolysis GDP Ras-GDP Pi

44 Ras GTPase Cycle GTP Ras-GTP H 2 O Guanine Nucleotide Exchange Factors (GEFs) GDP Ras-GDP GTPase Activating Proteins (GAPs) Pi -GAPs discovered biochemically -GEFs discovered genetically- first in yeast and then drosophila

45 Ras belongs to the larger family of small GTPbinding switch Small GTP-binding proteins: initiation & elongation factors (protein synthesis). Ras (growth factor signal cascades). Rab (vesicle targeting and fusion). ARF (forming vesicle coatomer coats). Ran (transport of proteins into & out of the nucleus). Rho (regulation of actin cytoskeleton) All GTP-binding proteins differ in conformation depending on whether GDP or GTP is present at their nucleotide binding site. Generally, GTP binding induces the active state.

46 Most GTP-binding proteins depend on helper proteins: GAPs, GTPase Activating Proteins, promote GTP hydrolysis. protein-gtp (active) GDP GEF GAP GTP P i protein-gdp (inactive) A GAP may provide an essential active site residue, while promoting the correct positioning of the glutamine residue of the switch II domain. Frequently a (+) charged arginine residue of a GAP inserts into the active site and helps to stabilize the transition state by interacting with (-) charged O atoms of the terminal phosphate of GTP during hydrolysis.

47 protein-gtp (active) GDP GEF GAP GTP P i protein-gdp (inactive) G a of a heterotrimeric G protein has innate capability for GTP hydrolysis. It has the essential arginine residue normally provided by a GAP for small GTP-binding proteins. However, RGS proteins, which are negative regulators of G protein signaling, stimulate GTP hydrolysis by G a.

48 protein-gtp (active) GDP GEF GAP GTP P i protein-gdp (inactive) GEFs, Guanine Nucleotide Exchange Factors, promote GDP/GTP exchange. The activated receptor (GPCR) serves as GEF for a heterotrimeric G protein.

49 Mutant Ras in Tumors Can t Hydrolyze GTP and Accumulates in the Active GTP-Bound State GTP Ras-GTP Exchange X GDP Ras-GDP

50 Ras Superfamily Ras Rho Rab Arf Ran H-Ras N-Ras K-Ras TC21 Rap1 Rap2 R-Ras RalA RalB RhoA RhoB RhoC RhoG RhoE CDC42 Rac1 Rac2 Rab 1-N Arf 1-6 Ran Growth/ Cytoskeleton Vesicle sorting Differentiation NuclearTranslocation

51 Functions of Ras Proteins 1) Promote Cell Proliferation -fibroblasts, epithelial cells, lymphocytes -mediate actions of growth factors 2) Promote Cell Differentiation -neuronal progenitor cells (PC12) -mediate action of neurotrophins 3) Contribute to Differentiated Cell Functions -CNS neurons -mediate effects of calcium signaling

52 Multiple Regulators of Ras Function Tyrosine Kinases SOS GRB2 Phospholipase C Ras-GRP DAG Ca 2+ Calmodulin Ras-GRF Ras Each GEF has motif that connects it to distinct upstream signals but similar catalytic domain that allows it to activate Ras

53 Multiple Effectors of Ras Function Ras Ral-GEF PI3Kinase Raf Ral PDK1 Akt Mek Exocyst RalBP Erk Src

54 Page 697 Structure of the Ras binding domain of Raf (RafRBD; orange) in complex with Rap1A GDPNP (=homolog of Ras light blue).

55 Page 700 Structure of Src ADPNP lacking its N-terminal domain and with Tyr 527 phosphorylated.

56 MAP kinase Pathway

57 Activation of Ras

58 Activation of MAPK cascade

59 Page 696 The Ras-activated MAP kinase cascade

60 Page 698 MAP kinase cascades in mammalian cells.

61 Scaffolding proteins help organize MAPKs

62 Page 699 Scaffold proteins that modulate mammalian MAP kinase cascades. (a) JIP-1(JNK-interacting protein).

63 Page 699 Scaffold proteins that modulate mammalian MAP kinase cascades. (b) MEKK1.

64 Insulin signalling Two extracellular alpha chains each with an insulin-binding site, linked to two transmembrane beta chains, each with a cytosolic tyrosine kinase domain. Following insulin binding to the alpha chains, the tyrosine kinase domain of each beta chain catalyzes autophosphorylation of tyrosine residues in the adjacent kinase domain. The tyrosine kinase domains also catalyze the phosphorylation of proteins called insulin-receptor substrates (IRSs). Some of the effects of insulin binding are mediated through the second messenger system of PIP3 which regulates several serine-threonine protein kinases. Binding of insulin in some cell types (e.g., muscle) leads to stimulation of phoshatase cascades leading to inactivation of glycogen phoshorylase in the glycogen degradation pathways

65 Insulin formation of PIP3 Binding of insulin to its receptor activates the protein tyrosine kinase activity of the receptor, leading to the phosphorylation of insulin-receptor substrates (IRSs). The phosphorylated IRSs interact with the phosphotidylinositide 3-kinase (PI kinase) at the plasma membrane, where the enzyme catalyzes the phophorylation of PIP2 to PIP3. PIP3 acts as a second messenger, carrying the message from extracellular insulin to certain intracellular protein kinases. Recent research has found that many of the effects of insulin on cells are mediated through PIP2. Whereas the inositol-phospholipid signalling system leads to hydrolysis of PIP2, insulin activates phophorylation of PIP2 to PIP3.

66 INSULIN SIGNALLING Figure Insulin signal transduction. Page 719 CAP: Cbl-associated protein C3G: a G-nucleotide exchange factor CrkII: a SH2/SH3 adapter protein PDK1: phophoinositide-dependent kinase mtor: target of rapamycin

67 Insulin Transduction

68 PI3K

69 Page 694 Structure of an insulin receptor substrate protein.

70 Protein Tyr Phosphatases SHP-2 Protein Ser/Thr Phosphatases PP1 PP2A PP2B (=calcineurin / target of immunosuppressant drugs) PP2C Protein Tyrosine Phosphatase SHP-2. Page 706 PP2A Structurally variable Functionally diverse Catalytic subunit ) Scaffold subunit (A)(PR65) Four different regulatory subunits (B, B, B, B ), bind to A & C subunits A subunit of PP2A.

71 Page 707 Calcineurin. (a) human FKBP12 FK506 CaN. Calcineurin. (b) human CaN with CaNA yellow, its autoinhibitory segment red, and CaNB cyan.

72 Abl-Akt

73 Page 703 Structure of the Abl PTK domain in complex with a truncated derivative of gleevec (anticancer drug).

74 Integrins-Pakcytoskeleton

75 Non-Receptor-Tyrosine kinases

76 Domain organization of the major NRTK subfamilies.

77 Page 701 Model of Src activation.

78 Page 702 The JAK-STAT pathway for the intracellular relaying of cytokine signals.

79 JAK- STAT

80 Jak- STAT

81 GPCR = G-protein coupled Receptors

82 G-protein linked receptors Ligand: Diverse ligands, such as epinephrine Receptor: Integral membrane protein with 7TM (7 transmembrane domains) G-protein: trimeric protein (α, β, γ) attached to the cell membrane by lipid anchors Effectors: Target proteins that show altered activity when they interact with activated G- protein subunits (α, or βγ)

83 G Protein Signal Cascade A hormone (e.g., epinephrine or glucagon) that activates formation of camp or IP3, binds at the cell surface to a receptor with 7 transmembrane α- helices. Rhodopsin was the first member of the family of 7-helix receptors to have its structure determined by X-ray crystallography. Rhodopsin PDB 1F88

84 Cytosolic domains of 7-helix receptors interact with G-proteins (=heterotrimeric GTP-binding protein). A G-protein has 3 subunits, designated α, β, γ. 7-Helix receptors that interact with G-proteins are called GPCR, or G-Protein-Coupled Receptors. Various proteins interact with GPCRs to modulate their activity. Effects of these interactions include: altered ligand affinity receptor dimerization that may enhance or alter activity altered receptor localization Ligand-induced receptor clustering may also regulate receptor function.

85 G-protein linked receptors and G-proteins Receptor G-protein

86 Interaction between receptor and G-protein Once the ligand binds, the activated receptor recruits a G-protein Nucleotide exchange occurs (GTP replaces GDP) and the trimer dissociates into 2 parts: -α subunit -βγ subunit Both parts can regulate downstream pathways

87 Variety of G-proteins Gs are stimulatory Gi/0 are inhibitory Gq act on PLC G12/13 act on ion channels 22 α subunits 5 β subunits 12 γ subunits

88 G s proteins are stimulatory Upon dissociation, a G s protein stimulates an effector enzyme, such as -adenylate cyclase, -phospholipase Cβ or -ion channels (K + or Ca 2+ ) Adenylate cyclase converts ATP to camp Elevated camp stimulates camp-dependent protein kinase (PKA) by inducing the release of inhibitory subunits

89 A G-protein that is part of a pathway that stimulates Adenylate Cyclase is called G s & its α subunit G sα. hormone signal outside GPCR plasma membrane α γ γ + α cytosol AC GDP β β GTP GTP GDP ATP camp + PP i The α subunit of a G-protein (G α ) binds GTP, & can hydrolyze it to GDP + P i. α & γ subunits have covalently attached lipid anchors that bind a G-protein to the plasma membrane cytosolic surface. Adenylate Cyclase (AC) is a transmembrane protein, with cytosolic domains forming the catalytic site.

90 hormone signal outside The complex of β & γ subunits G β,γ inhibits G α. GPCR plasma membrane α γ γ + α cytosol AC GDP β β GTP GTP GDP ATP camp + PP i The sequence of events by which a hormone activates camp signaling: 1. Initially G α has bound GDP, and α, β, & γ subunits are complexed together.

91 hormone signal outside GPCR plasma membrane α γ γ + α cytosol AC GDP β β GTP GTP GDP ATP camp + PP i 2. Hormone binding to a 7-helix receptor (GPCR) causes a conformational change in the receptor that is transmitted to the G protein. The nucleotide-binding site on G α becomes more accessible to the cytosol, where [GTP] > [GDP]. G α releases GDP & binds GTP (GDP-GTP exchange).

92 hormone signal outside GPCR plasma membrane α γ γ + α cytosol AC GDP β β GTP GTP GDP ATP camp + PP i 3. Substitution of GTP for GDP causes another conformational change in G α. G α -GTP dissociates from the inhibitory βγ complex & can now bind to and activate Adenylate Cyclase.

93 hormone signal outside GPCR plasma membrane α γ γ + α cytosol AC GDP β β GTP GTP GDP ATP camp + PP i 4. Adenylate Cyclase, activated by G α -GTP, catalyzes synthesis of camp. 5. Protein Kinase A (camp Dependent Protein Kinase) catalyzes phosphorylation of various cellular proteins, altering their activity.

94 G-protein dissociation

95 GTP hydrolysis ends signaling and induces trimerization

96 The stimulatory G sα, when it binds GTP, activates Adenylate cyclase. An inhibitory G iα, when it binds GTP, inhibits Adenylate cyclase. Different effectors & their receptors induce G iα to exchange GDP for GTP than those that activate G sα. In some cells, the complex of G β,γ that is released when G α binds GTP is itself an effector that binds to and activates other proteins.

97 Variety of G-proteins Gs are stimulatory Gi/0 are inhibitory Gq act on PLC G12/13 act on ion channels 22 α subunits 5 β subunits 12 γ subunits

98 VARIETY OF G-PROTEINS: Gα, -β, -γ

99

100 ADP-Ribosylation Cholera toxin catalyzes covalent modification of G sα. ADPribose is transferred from NAD + to an arginine residue at the GTPase active site of G sα. This ADP-ribosylation prevents G sα from hydrolyzing GTP. Thus G sα becomes permanently activated. Pertussis toxin (whooping cough disease) catalyzes ADPribosylation at a cysteine residue of G iα, making the inhibitory G α incapable of exchanging GDP for GTP. Thus the inhibitory pathway is blocked. ADP-ribosylation is a general mechanism by which activity of many proteins is regulated, in eukaryotes (including mammals) as well as in prokaryotes.

101 Page 680 Figure Cholera Toxin composition = AB 5 B:103AA / A: 240AA Mechanism of action of cholera toxin. Activation: clivage en A 1 (195AA) + A 2 (45AA) reliés par -S-S- A pénètre dans cellule (endocytose) / dirigé dans ER: liaison par séquence KDEL de A 2 Effet: ADP-ribosylation de Arg de Gsα

102 ADP-RIBOSILATION BY PERTUSSIS TOXIN ADP-ribosylation de Cys sur Giα

103 ADP ribosylation o O O o O P o O o o P O NAD + o O o O (nicotinamide adenine dinucleotide) CH2 2 H H OH N N CH2 2 Oo H H OH + N Oo H H OH NH2 2 Arg residue H H OH HNH2 Oo C NH2 o N N protein (CH 2 ) 3 NH C NH 2 + NH 2 o O O O P O O CH2 2 H H OH N N o P Oo CH2 2 Oo Oo H H OH HNH2 Oo C NH2 + N H o o o nicotinamide protein (CH C 2 ) 3 NH NH2 Oo H H OH NH2 2 N N H H OH + C NH 2 ADP-ribosylated protein

104 VARIETY OF G-PROTEINS: Gα, -β, -γ

105 Structure of G proteins: The nucleotide binding site in G α consists of loops that extend out from the edge of a 6-stranded β-sheet. Three switch domains have been identified, that change position when GTP substitutes for GDP on G α. GTPγS PDB 1GIA Inhibitory G α These domains include residues adjacent to the terminal phosphate of GTP and/or the Mg ++ associated with the two terminal phosphates.

106 H H O O O GTP hydrolysis O N P O P O P O CH 2 O O O O N O O O H H H OH H OH O O N N N NH NH2 2 GTP hydrolysis occurs by nucleophilic attack of a water molecule on the terminal phosphate of GTP. Switch domain II of G α includes a conserved glutamine residue that helps to position the attacking water molecule adjacent to GTP at the active site.

107 PDB 1GP2 PDB 1GP2 G β face view of β-propeller G β - side view of β-propeller The β subunit of the heterotrimeric G Protein has a β-propeller structure, formed from multiple repeats of a sequence called the WD-repeat. The β-propeller provides a stable structural support for residues that bind G α.

108 Adenylate Cyclase catalyzes: ATP camp + PP i Binding of certain hormones (e.g., epinephrine) to the outer surface of a cell activates Adenylate Cyclase to form camp within the cell. Cyclic AMP is thus considered to be a second messenger. camp O O O O N H 2 5' C 4' C P P H O O- N O NH 2 N O H H O N 3' NH2 O N H OH 2' N N 1'

109 Protein Kinase A (camp-dependent Protein Kinase) transfers P i from ATP to OH of a Ser or Thr in a particular 5-amino acid sequence. Protein Kinase A in the resting state is a complex of: 2 catalytic subunits (C) 2 regulatory subunits (R) : R 2 C 2

110 Each regulatory subunit (R) of Protein Kinase A contains a pseudosubstrate sequence, like the substrate domain of a target protein but with Ala substituting for the Ser/Thr. The pseudosubstrate domain of (R), which lacks a hydroxyl that can be phosphorylated, binds to the active site of (C), blocking its activity. When each (R) binds 2 camp, a conformational change causes (R) to release (C). Each catalytic subunit can then catalyze phosphorylation of Ser or Thr on target proteins. R 2 C camp R 2 camp C

111 R 2 C camp R 2 camp C AKAPs, A-Kinase anchoring proteins, bind to the regulatory subunits (R) of Protein Kinase A. AKAPs localize Protein Kinase A to specific regions of a cell. PKIs, Protein Kinase Inhibitors, modulate activity of the catalytic subunit (C).

112 PKA activation by camp

113 PKA activates gene expression

114 CREB = camp responsive Elements Binding Protein

115 EXAMPLE _ Glycogen Metbolism

116 Gs & Gi Pathways

117 Inactivation of PKA pathway The G-protein -PKA pathway is inactivated by: Receptor desensitization (phophorylation by PKA) GTP hydrolysis in G-protein (GTPase of a-subunit) camp hydrolysis by phosphodiesterase PKA inhibition Phosphatase action on PKA targets Activation of an antagonistic pathway (G i )

118 Turn off of the signal: 1. G α hydrolyzes GTP to GDP + P i. (GTPase). The presence of GDP on G α causes it to rebind to the inhibitory βγ complex. Adenylate Cyclase is no longer activated. 2. Phosphodiesterase catalyzes hydrolysis of camp AMP.

119 Turn off of the signal (cont.): 3. Hormone Receptor desensitization occurs. This process varies with the hormone. Some receptors are phosphorylated via G- protein-coupled receptor kinases. The phosphorylated receptor may then bind to a protein arrestin that blocks receptor-gprotein activation & promotes removal of the receptor from the membrane by clathrinmediated endocytosis. 4. Protein Phosphatase catalyzes removal by hydrolysis of phosphates that were attached to proteins via Protein Kinase A.

120 Phosphodiesterase enzymes catalyze: camp + H 2 O AMP The phosphodiesterase that cleaves camp is activated by phosphorylation catalyzed by Protein Kinase A. camp N N NH 2 NH2 N N N N N N Thus camp stimulates its own degradation, leading to rapid turnoff of a camp signal. O O O O H 2 5' C 4' C P P O H O- H O O 3' O O H H OH 2' 1'

121 G-protein coupled Receptor

122 ARRESTIN Model for interaction of β-loop with Arrestin

123 Novel roles of endocytosis and scaffolding in signal propagation H Kholodenko B.N. (2002) Trends Cell Biol. 12: 173.

124 Signal amplification is an important feature of signal cascades: One hormone molecule can lead to formation of many camp molecules. Each catalytic subunit of Protein Kinase A catalyzes phosphorylation of many proteins during the life-time of the camp.

125 PLCβ & PKC

126 G-proteins and phospholipases Some G-proteins activate PLCβ (phospholipase Cβ), triggering formation of inositol triphosphate (IP 3 ) and diacylglycerol (DAG)

127 DAG, IP3, Ca 2+ and signal transduction DAG: substrate for production of eicosanoids, potent signaling molecules including arachadonic acid activates PKC IP3: induces release of Ca 2+ from ER stores via IP3- sensitive Ca-channels Ca 2+ : Elevated Ca 2+ can activates PKC and CamK.

128 Phosphatidylinositol Signal Cascades HO R 1 O O H 2 C O C C RO C C C CH H 2 C phosphatidylinositol R RO HO 2 O OH H O C O P O OH R 2 O 1 6 H OH OH H 3 OH H OH H 4 OH OH OH H 5 Some hormones activate a signal cascade based on the membrane lipid phosphatidylinositol.

129 IP3 as second messenger - Phosphatidylinositides Page 707 Molecular formula of the phosphatidylinositides.

130 Page 714 Flow chart of reactions in the synthesis of phosphoinositides in mammalian cells.

131 Page 714 Domain organization of the 3 classes of PI3Ks.

132 HO R 1 O O HH 2 C O C 2 C O C C C R C C R OO R 2 R 2 O CH CH O O H 2 O P O H 2 C RO P O O H O 1 6 OH H OH 1 6 HOH H OH 2 OHH H OH 2 OH H H H 3 4 H 2 H3 OPO 4-4,5-bis-Ph 3 OH H OH PIP phosphatidylinositol 2 phosphatidylinositol- 4,5-bisphosphate OPO 3 2 Kinases sequentially catalyze transfer of P i from ATP to OH groups at positions 5 & 4 of the inositol ring, to yield phosphatidylinositol-4,5-bisphosphate (PIP 2 ). PIP 2 is cleaved by the enzyme Phospholipase C. O C O OH 5 OPO3H OH H 5 OPO3H

133 Page 709 A phospholipase is named according to the bond that it cleaves on a glycerophospholipid.

134 Different isoforms of PLC have different regulatory domains, & thus respond to different signals. One form of PLC is activated by a G-protein, G q. O R 1 O O H 2 C O C C A GPCR (receptor) is activated. GTP exchanges for GDP. G qa -GTP activates Phospholipase C. Ca ++, which is required for activity of Phospholipase C, interacts with negatively charged residues & with phosphate moieties of IP 3 at the active site. RO C C C CH H 2 C cleavage by Phospholipase C R RO PIP 2 phosphatidylinositol- 4,5-bisphosphate 2 O C O OP O O OH H R 2 O 1 6 H OH 3 H H OH H OPO3 OPO 3 2 H 4 2 OPO 3 OPO3 5

135 2 OH OPO3 H OPO H OH 3 H OPO3 H OH H OPO 3 2 H 4 2 OPO 3 OPO3 IP 3 inositol-1,4,5-trisphosphate 5 HO R 1 O O H 2 C O C C RO CH H 2 C diacylglycerol C C C R OH OH O C OH R 2 Cleavage of PIP 2, by PLC, yields two 2nd messengers: inositol-1,4,5-trisphosphate (IP 3 ) & diacylglycerol (DG). Diacylglycerol, with Ca ++, activates Protein Kinase C, which catalyzes phosphorylation of several cellular proteins, altering their activity.

136 Page 708 Role of PIP 2 in intracellular signaling.

137 Page 709 Domain organization of the four classes of phosphoinositide-specific PLCs.

138 Page 713 Activation of PKC.

139 Ca ++ calmodulin IP 3 Ca ++ -release channel Ca ++ endoplasmic reticulum ATP Ca ++ Ca ++ -ATPase ADP + P i IP 3 activates Ca ++ -release channels in ER membranes. Ca ++ stored in the ER is released to the cytosol, where it may bind calmodulin, or help activate Protein Kinase C. Signal turn-off includes removal of Ca ++ from the cytosol via Ca ++ -ATPase pumps, & degradation of IP 3.

140 OPO3 OH H OH H OPO 3 2 H H OPO3 OPO3 OH H OPO 3 2 H OPO 3 2 (3 steps) Sequential dephosphorylation of IP 3 by enzymecatalyzed hydrolysis yields inositol, a substrate for synthesis of PI. IP 3 may instead be phosphorylated via specific kinases, to IP 4, IP 5 or IP 6. Some of these have signal roles. E.g., the IP 4 inositol-1,3,4,5-tetraphosphate in some cells activates plasma membrane Ca ++ channels. OH H OH H OH IP 3 inositol H H OH H OH OH H + 3 P i

141 O R 1 O O H 2 C O C C RO C C H 2 C CH C phosphatidyl- inositol- 3-phosphate R O The kinases that convert PI (phosphatidylinositol) to PIP 2 (PI-4,5-P 2 ) transfer P i from ATP to OH at positions 4 & 5 of the inositol ring. PI 3-Kinases instead catalyze phosphorylation of phosphatidylinositol at the 3 position of inositol ring. 2 O C O P O O OH H O R 2 O 1 6 H OPO H H OH H OPO3 OH OH H 5

142 O R 1 O O H 2 C O C C RO H 2 C CH phosphatidyl- inositol- 3-phosphate 2 O O C R C C C RO O O P O O OH H OH R 2 O 1 6 H OPO H OH H OPO3 H OH OH H 5 PI-3-P, PI-3,4-P 2, PI-3,4,5-P 3, & PI-4,5-P 2 have signaling roles. These are ligands for particular pleckstrin homology (PH) and FYVE protein domains that bind proteins to membrane surfaces.

143 PKB (Protein Kinase B, also called Akt) becomes activated when it is recruited from the cytosol to the plasma membrane surface by binding to products of PI-3 Kinase, e.g., PI-3,4,5-P 3. Other kinases at the cytosolic surface of the plasma membrane then catalyze phosphorylation of PKB, activating it. Activated PKB catalyzes phosphorylation of Ser or Thr residues of many proteins, with diverse effects on metabolism, cell growth, and apoptosis. Downstream metabolic effects of PKB include stimulation of glycogen synthesis, stimulation of glycolysis, and inhibition of gluconeogenesis.

144 Signal cascades may be mediated by complexes of proteins that assemble at the cytosolic surface of the plasma membrane, frequently in areas of distinct lipid composition called lipid rafts. Signal proteins may be recruited into such complexes by insertion of their lipid anchors in the plasma membrane, interaction with membrane-associated scaffolding proteins, or interaction of their pleckstrin homology domains with transiently formed PI derivatives.

145 Interactions between G-proteins and RTKs

146 Summary on Enzyme-linked receptors Enzyme-linked receptors generate variable cellular responses Multiplicity of players (receptors, kinases etc) arise from gene duplication and divergence Recognize the critical role of phosphorylation/ dephosphorylation control as molecular switches Adaptor molecules allow construction of protein signaling cascades with variable outputs

147 JAK-STAT

148 JAK-STAT

149 cgmp Pathway

150

151

152

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