Cell Signaling I Signaling molecules and their receptors Cell Biology Lecture 12

Readings and Objectives 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

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

Signaling by secreted molecules 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

Animation: Types of Signaling

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

1. Hydrophobic signaling molecules 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

2. Neurotransmitters 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

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

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

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

Signaling Receptors 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.

Animation: Signal amplification

Intracellular receptors: Nuclear Receptors 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 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

Membrane receptors: G-protein coupled receptros largest family of cell surface receptors seven membrane-spanning α helices 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 Ligand binding, conformational change, cytosolic domain activates a G protein heterotrimeric G proteins : α, β, and γ subunits α- binds G-nucleotides, regulate G protein activity In inactive state, α bound to GDP in a complex with β, and γ ligand binding causes GTP to replace GDP The α and βγ complex then dissociate from the receptor and interact with their targets A large array of G proteins connect receptors to distinct targets. G proteins can also regulate ion channels

Animation: G-protein coupled receptors

Receptor Protein- Tyrosine Kinases 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 α helix a cytosolic C-terminal domain with protein-tyrosine kinase activity

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

Receptor Protein- Tyrosine Kinases

Nonreceptor protein-tyrosine kinases 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) Cytokines regulate development and differentiation of lymphocytes during immune response

Non-receptor protein-tyrosine kinases 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