Cell signalling 26 March 2007
Overview • No cell lives in isolation • In all multicellular organisms, survival depends on an elaborate intercellular communication network that coordinates the growth, differentiation, and metabolism of the multitude of cells in diverse tissues and organs. • Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases can be treated effectively and, theoretically, artificial tissues could be built.
Cells within small groups often communicate by direct cell-cell contact. Specialized junctions in the plasma membranes of adjacent cells permit them to exchange small molecules and to coordinate metabolic responses; other junctions between adjacent cells determine the shape and rigidity of many tissues. • In addition, the establishment of specific cell-cell interactions between different types of cells is a necessary step in the development of many tissues. In some cases a particular protein on one cell binds to a receptor protein on the surface of an adjacent target cell, triggering its differentiation.
Eukaryotic microorganisms • Pheromones coordinate • Sexual mating • Differentiation • Plants, animals • Extracellular signaling controls • Metabolic processes • Growth and differentiation • Protein synthesis
Signal molecules produce responses in target cells that have receptors. • In multicellular organisms • Chemicals • Small molecules (aa., lipid derivatives) • Peptides • proteins • Some diffuse and bind to intracellular receptors • Steroids, retinoids, thyroxine
Signal transduction • Overall processes converting a signal into cellular responses
Cell Signaling • Steps involved are: • Synthesis • Release from signaling cells • Transport to target cells • Binding to receptor and activation • Signal transduction by activated receptor • Specific changes • Removal of signal (termination)
Receptor activation • Secreted or membrane bound molecules • Hormones, growth factors, neurotransmitters, pheromones • Changes in the concentration of metabolites • Oxygen or nutrients • Physical stimuli • Light, touch, heat
Three types of signaling in animals • Endocrine • hormones • Paracrine • Neurotransmitters • Growth factors • Autocrine • Growth factors (cultured cells, tumor cells)
Ligand binding and effector specificity • Each receptor binds only a single ligand or a group of closely related molecules. However, many signaling molecules bind to multiple types of receptors • Acetylcholine binds to different receptors on muscle cells (contraction), heart muscle cells (inhibition of contraction) and pancreas acinar cells (exocytosis of secretory granules), respectively
Different receptors of the same class that bind different ligands generate the same cellular response • In liver, ACTH, epinephrine and glucagon bind to different GPCRs; but all three activate the same signaling pathway (cAMP)
Intracellular signal transduction • Many receptors transmit signals via second messengers • They rapidly alter the activity of enzymes or non-enzymatic proteins • Ca2+ triggers contraction in muscle cells • Exocytosis of secretory vesicles in endocrine cells • cAMP generates different metabolic changes in different type of cells
Regulation of signaling • External signal decreases • Degradation of second mesenger • Desensitization to prolonged signaling • Receptor endocytosis • Modulation of receptor activity • Phosphorylation • Binding to other proteins
Hormones Can Be Classified Based on Their Solubility and Receptor Location • Most hormones fall into three broad categories: • (1) small lipophilic molecules that diffuse across the plasma membrane and interact with intracellular receptors; • (2) hydrophilic or (3) lipophilic molecules that bind to cell-surface receptors. • Recently, nitric oxide, a gas, has been shown to be a key regulator controlling many cellular responses
Classification of receptors • Intracellular receptors (for lipid soluble messengers) • function in the nucleus as transcription factors to alter the rate of transcription of particular genes. • Plasma membrane receptors (for lipid insoluble messengers) • Receptors function as ion channels • receptors function as enzymes or are closely associated with cytoplasmic enzymes • receptors that activate G proteins which in turn act upon effector proteins, either ion channels or enzymes, in the plasma membrane.
Intracellular Receptors • Extracellular signal molecules are small, lipid-soluble hormones such as steroid hormones, retinoids, thyroid hormones, Vitamin D. (Made from cholesterol) • These hormones diffuse through plasma and nuclear membranes and interact directly with the transcription factors they control.
Sequence similarities and three functional regions • N-terminal region of variable length (100-500 aa); in some receptors portions of this region act as activation domain • At the center, DNA binding domain, made of a repeat of C4-zinc finger motif • Near the C-terminal end, an hormone binding domain, which may act as an activation or repression domain.
Nuclear receptor response elements • Some characteristic sites of DNA are called response elements and can bind several nuclear receptors. • These repeat regions are arranged either as an invert repeat, or direct repeat. • Inverted repeat: glucocorticoid response element; estrogen response element • Repeats are separated by any three bases, implicating symmetrical binding of the receptor homodimer to DNA
Receptors for vitaminD, retinoic acid and thyroid hormone bind to direct repeats as heterodimers, • Second component of the heterdimer is RXR monomer (i.e, RXR-RAR; RXR-VDR) • The specifity of the binding is determined by the spacing between repeats.
Regulation of transcription activity • Regulatory mechanisms differ for hetero-dimeric and homodimeric receptors • Heterodimeric receptors are exclusively nuclear; without ligand, they repress transcription by binding to their cognate sites in DNA • They do so by histone deacetylation
Homodimeric receptors are cytoplasmic in the absence of ligands. • Hormone binding leads to nuclear translocation of receptors • Absence of hormone causes the aggregation of receptor as a complex with inhibitor proteins, such as Hsp90
Early primary response (A) and delayed secondary response (B) that result from the activation of an intracellular receptor protein.