Receptor Signaling Mechanisms (M Law) PDF

Molecular Drug Targets Enzymes 28% Hormones & Factors 11% Receptors 45% Ion Channels 5% DNA 4% Unknown 7% Heterotrimeric G Proteins Receptor GTP...

Molecular Drug Targets Enzymes 28% Hormones & Factors 11% Receptors 45% Ion Channels 5% DNA 4% Unknown 7% Heterotrimeric G Proteins Receptor GTP a b g Heterotrimeric GDP G protein  GPCR Components Receptors Ligands: > 800 Hormones, Neurotransmitters, Chemokines, Ions, Amino acids, Peptides, etc. G-proteins (abg) a-20 b(6)g(12) Gas- AC Gai - AC Gaq - PLC Why use G proteins? Means of amplifying the signal G proteins can regulate more than one effector An example of a signal transduction cascade involving cyclic AMP The binding of adrenaline to an adrenergic receptor initiates a cascade of reactions inside the cell. The signal transduction cascade begins when adenylyl cyclase, a membrane- bound enzyme, is activated by G-protein molecules associated with the adrenergic receptor. Adenylyl cyclase creates multiple cyclic AMP molecules, which fan out and activate protein kinases (PKA, in this example). Protein kinases can enter the nucleus and affect transcription. © 2010 Nature Education  PKA phosphorylates multiple proteins which regulate a wide variety of intracellular events Phosphorylase PKA CREB Kinase (Gene (Glycogen Transcription) Breakdown) Hormone Sensitive L-Type Lipase Ca Channels (Triglyceride (Heart Pyruvate Breakdown) Contraction) Kinase (Glycolysis) activated PKC  There is no second messenger in kinase-linked receptor signaling General mechanism of peptide hormone, growth factor action : G protein coupled receptor Receptor Second Messenger Hormone (eg. Insulin) PM Change in kinase and/or phosphatase activity Protein kinase-linked receptors 1. Receptors associated with cytosolic kinases (eg. Prolactin) 2. Receptor tyrosine kinases (eg. Insulin) 3. Receptor serine/threonine kinases (eg. TGF-b) Ligands Prolactin Receptors associated with cytosolic kinases GH Interferons Cytokines Ligand JAK JAK P JAK JAK P P JAK JAK P P P P P P P P SH2 P P STAT P X X = SHC GRB2 Dimerization Downstream kinase PLCg and nuclear cascades PI3K translocation Transcription  Receptor tyrosine kinases Receptor tyrosine kinases (RTKs) consist of an extracellular ligand binding and dimerization domain, a single hydrophobic transmembrane a-helix and a cytosolic domain with intrinsic tyrosine kinase activity Two types 1. Single transmembrane spanning proteins that dimerize when ligand binds (EGF receptor, PDGF receptor) 2. Covalently linked dimers (Insulin receptor, IGF-1 receptor) Cartoon representation of the 58 RTKs grouped into 20 RTK subfamilies.. *The LMTK proteins were predicted to be tyrosine kinases, but later experiments demonstrated that they only have serine/threonine kinase activity. If they are not counted as RTKs, there are only 55 total RTKs and 19 RTK subfamilies in humans. Published in: Michael D. Paul; Kalina Hristova; Chem. Rev. Ahead of Print DOI: 10.1021/acs.chemrev.8b00467 Copyright © 2018 American Chemical Society  Insulin a a a a b b b b P-Y P-Y Y Y IRS 1-4 IRS 1-4 Y Y P-Y P-Y GRB2/mSOS p21Ras PI3- Raf-1 kinase mTOR MEK MAPK PKB/Akt SGK p70S6K aPKC Cell growth DNA synthesis Early response Protein translocation Enzyme activity Gene transcription genes  PKB/Akt phosphorylates multiple proteins which Insulin regulate a wide variety of intracellular events a a b b IRS PI-3 Kinase PKB/Akt PDK1/2 proteins Glycogen Synthesis GSK-3 ?? Fox Stimulated Transcription factors 6PF2K GLUT4 Protein Transcription Synthesis of Specific Stimulated Glycolysis Glucose Stimulated Genes Transport Inhibited Stimulated Receptor serine/threonine kinases  The Nuclear Receptor Subfamily Six structural domains A/B C D E F AF-1 DBD Hinge LBD AF-2 Receptors: Steroid class RXR partnered Orphans GR, MR, PR TR, RAR, VDR COUP-TF, HNF-4 AR, ER PPAR a, b, g Ligand: Steroids 9-Cis RA + X ?? AF = Activation function  AFE E HR AF R R FE A to r/ AF tiv a r oac resso C ep r Co e ne gion BTM G re g d in co AFE = Accessory Factor Element AF = Accessory Factor HRE = Hormone Response Element BTM = Basal Transcription Machinery Cytoplasm + + TRE TRE TRE GRE GRE GRE + + Nucleus  + + Cytoplasm HRE HRE HRE Nucleus mRNA synthesis Protein synthesis Cellular effects  Additional Receptor Signaling Mechanisms Nitric Oxide (NO) Receptors The Notch Signaling Pathway  NO Receptors The signaling functions of NO begin with its binding to protein receptors on or in the cell. The binding sites can be either: a metal ion in the protein or one of its S atoms (e.g., on cysteine). In either case, binding triggers an allosteric chance in the protein which, in turn, triggers the formation of a "second messenger" within the cell. The most common protein target for NO is soluble guanylyl cyclase, an enzyme that generates the second messenger cGMP. Roy, B. et al. J. Biol. Chem. 2008;283:18841-18851 Notch signaling pathway, and domain organization of Notch receptors and DSL ligands Gordon, W. R. et al. J Cell Sci 2008;121:3109-3119 Fig. 1. Notch signaling pathway, and domain organization of Notch receptors and DSL ligands. (A) Model for the major events in the Notch signaling pathway. Signals initiated by the engagement of ligand (1) lead to metalloprotease (MP) cleavage at site S2 (2). This proteolytic step allows the cleavage of Notch by the g-secretase complex at site S3 within the transmembrane domain (3) and release of intracellular notch (ICN) from the membrane. ICN translocates to the nucleus (4), where it enters into a transcriptional activation complex with CSL and MAM, inducing the transcription of target genes (5).