Cell Signaling I Signaling molecules and their receptors

1. Cell SignalingISignaling molecules and their receptors Cell Biology Lecture 12

2. Readings and Objectives • Reading • Russell Chapter 8 (not sufficient) • Cooper: Chapter 15 • Topics Lecture 12 • Signaling Molecules and Their Receptors • Functions of Cell Surface Receptors Lecture 13 • Pathways of Intracellular Signal Transduction • Signal Transduction and the Cytoskeleton • Signaling Networks

3. Cell Signaling Introduction regulate virtually all aspects of cell behavior Cell proliferation, metabolism, organellar and cell movement, apoptosis, etc Modes of cell signaling Direct cell-cell signaling—direct interaction of a cell with its neighbor Signaling by secreted molecules—signals are transmitted over distant cells signaling molecules from one cell bind to receptors on other cells range in complexity from simple gases to proteins

4. Endocrine signaling—signaling molecules (hormones), target cells at distant body sites Example: estrogen. Paracrine signaling—act on neighboring target cells, e.g., neurotransmitters Autocrine signaling—respond to self signaling molecules T lymphocytes: proliferation in response to cytokines produced by the same cell Signaling by secreted molecules

5. Animation: Types of Signaling

6. Classes of signaling molecules Hydrophobic signaling molecules Use nuclear receptors Neurotransmitters Peptide signaling molecuels Eicosanoids 2 through 4 use membrane receptors Signaling molecules

7. Passively diffuse across cell membrane Steroid hormones Vitamin D3 Thyroid hormone Retinoid acid Nitric oxide and CO All use intracellular receptors function as activators or repressors of genes 1. Hydrophobic signaling molecules

8. carry signals between neurons, from neurons to other target cells hydrophilic, can’t cross the plasma membrane of target cells; bind to cell surface receptors receptors ligand-gated ion channels Neurotranmitter binding opens the channels 2. Neurotransmitters

9. Peptide hormones Neuropeptides polypeptide growth factors Short polypeptides, one or more chains Variety of functions All use cell membrane anchored receptors 3. Peptide signaling molecules

10. Eicosanoids: lipid signaling molecules which include prostaglandins, prostacyclin, thromboxanes, and leukotrienes Arachindonic derived from phospholipids, by phospholypase A2 4. Eicosanoids: lipid signaling molecules

11. Cyclooxygenases catalyse the conversion (targets for anti-inflammatory drugs) Short lived, thus act in autocrine or paracrine pathways Platelet aggregation, inflammation, smooth muscle contraction 4. Peptide signaling molecules

12. Two types Intracellular receptors: include nuclear receptor family bind hydrophobic signaling ligands Conformation change, translocate to nucleus Act as transcriptional activators or repressors to regulate gene expression Signal does not amplify Membrane integral receptors: Bind non-hydrophobic signaling ligands Conformational change activates a phospho-relay cascade through kinases; might rely on secondary signaling molecules Exponential signal amplification through kinase cascade Targets: transcription, replication, translation, cytoskeleton remodeling, metabolic modulation, etc. Signaling Receptors

13. Animation: Signal amplification

14. Nuclear receptor superfamily Transcription factors, have domains for ligand binding DNA binding modulate transcription transcriptional activators or repressors Glucocorticoid receptor: bound to Hsp90 chaperones in the absence of hormone Glucocorticoid binding displaces Hsp90; binds the regulatory DNA sequences together with HAT coactivator(Histon acetyl transferase) Intracellular receptors: Nuclear Receptors

15. Thyroid hormone Hormone binding may alter the activity of the receptor: In the absence of hormone hormone receptor is associated with a corepressor complex (HDAC) No transcription of target genes Hormone binding, replaces HDAC with HAT (activator) Transcription is activated Intracellular receptors: Nuclear Receptors

16. largest family of cell surface receptors seven membrane-spanning αhelices Various signaling ligands, Hormones neurotransmitters Signals transmitted via guanine nucleotide-binding proteins (G proteins) Various targets and effector proteins Membrane receptors: G-protein coupled receptros

17. Ligand binding, conformational change, cytosolic domain activates a G protein heterotrimeric G proteins : α, β, and γsubunits α- binds G-nucleotides, regulate G protein activity In inactive state, αbound to GDP in a complex with β, and γ ligand binding causes GTP to replace GDP The αand βγcomplex then dissociate from the receptor and interact with their targets A large array of G proteins connect receptors to distinct targets. G proteins can alsoregulate ion channels Membrane receptors: G-protein coupled receptros

18. Animation: G-protein coupled receptors

19. Humans have 59 receptor RPTK Signaling molecules: EGF, NGF, PDGF, and other growth factors and insulin phosphorylate their substrate proteins on tyrosine residues Structure N-terminal extracellular ligand-binding domain single transmembrane αhelix a cytosolic C-terminal domain with protein-tyrosine kinase activity Receptor Protein- Tyrosine Kinases

20. Ligand-induced receptor dimerization Ligand binding activates the cytosolic kinase domain Autophosphorylation of receptor increases protein kinase activity creates binding sites for other proteins that transmit signals downstream of the activated receptors Receptor Protein- Tyrosine Kinases

21. SH2 domains mediate binding/activation of downstream signaling molecules Signal propagates down to final target through kinase cascade Receptor Protein- Tyrosine Kinases

22. Receptor Protein- Tyrosine Kinases

23. Similar RPTK, but the cytosolic domains have no catalytic activity Cytokine receptor superfamily(interleukin-2 and erythropoietin) Cytokine receptors function in association with non-receptor protein-tyrosine kinases Example: Janus Protein-tyrosine kinases (JAK) Cytokinesregulate development and differentiation of lymphocytes during immune response Nonreceptor protein-tyrosine kinases

24. Ligand binding induces receptor dimerization cross-phosphorylation of the associated nonreceptor protein-tyrosine kinases Phosphorylation of receptor cytosolic domains Formation of binding pocket for phosphorylation of other signaling proteins in the cascade Non-receptor protein-tyrosine kinases