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Cell Biology Lecture No. 21.docx

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Biology 2382B
Sashko Damjanovski

Cell Biology Lecture No. 21: Cell Signalling Wednesday March 27 , 2013h Signal Transduction & Its Players: -Signal transduction is the conversion of one signal into another and it involves the external stimulus of growth factors, cytokines, hormones, the ECM, neurotransmitters, light, sound, etc. The field of signal transduction is incredibly broad as it covers all aspects of normal development and physiology in cells. Understanding how signal transduction works can give us insight as to how certain diseases such as cancer and heart disease are initiated. Important players in signal transduction include: Receptor Tyrosine Kinases (RTKs), G-protein Coupled Receptors, proto-oncogenes (e.g. Ras), and Mitogen Activated Protein Kinases (MAPKs). Basic Elements Of Cell Signalling: -No human cells live in isolation, which is why communication between cells is often mediated mainly by extracellular signal molecules. All cells receive and respond to signals from their environment. Signals or signalling molecules (referred to as ligands or primary messengers) are an essential element of cell signalling pathways and can be: small molecules (e.g. organic chemicals the body produces like epinephrine and acetylcholine, peptide hormones like insulin, or monoamines that act like neurotransmitters) or large molecules (e.g. growth factors, cytokines, etc.). Receptors (both cell-surface and intracellular) are another important component of cell signalling as they transmit signals by interacting with other effector proteins (causing them to change their function or activity) or second messengers (e.g. Ca , cAMP, cGMP, IP , 3 DAG, NO, etc.). -During intracellular reception, a small signal molecule with hydrophobic properties reaches a target cell with the help of a carrier protein. The signal molecule will then dissociate from the carrier protein, cross the membrane and bind an intracellular receptor protein (in the cytoplasm or nucleus) so the signal can be transmitted. During cell-surface reception, a large hydrophilic signal molecule will bind a cell-surface receptor protein and the signal will be transmitted inside the cell through a series of biochemical processes. Nuclear-Receptor Superfamily: -Lipid-soluble hormones bind to intracellular receptors which constitute the nuclear-receptor superfamily of transcription factors. Most of these hormones are steroid hormones which derive from cholesterol and are synthesized by the adrenal glands. The proteins in this nuclear- receptor superfamily have highly conserved DNA- and ligand-binding domains along with a variable region for specificity. Some of the proteins in this superfamily are found in the cytoplasm (estrogen receptor, progesterone receptor, glucocorticoid receptor), while others are found in the nucleus (thyroxine receptor, retinoic acid receptor). Gene Activation By A Nuclear Receptor: -The characteristic nucleotide sequences of the DNA sites that bind nuclear receptors are called response elements. In the absence of the glucocorticoid hormone, the glucocorticoid receptor is trapped in the cytoplasm by inhibitor proteins (e.g. HSP90) that bind to its ligand-binding domain. The binding of the glucocorticoid hormone to a glucocorticoid receptor releases the inhibitor protein, allowing the receptor to enter the nucleus. Once inside the nucleus, the receptor binds to a response element of the target gene and stimulates the pre-initiation complex assembly required for gene transcription (accomplished by the receptor’s activation domain). Note that in order for the receptor to bind its response element in the nucleus (through its DNA-binding domain) it must first dimerize with another glucocorticoid receptor. Basic Concepts Of Signal Transduction: -The primary messenger (extracellular signal molecule) will bind a specific cell-surface receptor protein and this will initiate a cascade of different secondary messengers (intracellular signalling proteins or molecules) to transmit that signal inside the cell. These secondary messengers will interact with different types of effector proteins responsible for carrying out a specific physiological change in the cell. E.g. metabolic enzyme bringing about altered metabolism, gene regulatory protein giving rise to altered gene expression or a cytoskeletal protein altering cell shape or movement. Four Forms Of Intercellular Signalling: -There are four basic forms when it comes to intercellular signalling: endocrine signalling (signalling to distant cells), paracrine signalling (signalling to nearby cells), autocrine signalling (a cell signalling itself) and signalling by plasma membrane-attached proteins. In endocrine signalling, the signal molecules are synthesized and secreted by endocrine cells (signalling cells) and transported through the circulatory system to target cells (the term hormone generally refers to signalling molecules that mediate endocrine signalling). In paracrine signalling, the signalling molecules released by a cell affect only those target cells in close proximity (e.g. neurotransmitters). In autocrine signaling cells respond to substances that they themselves release. In “cell-cell” signalling by plasma membrane-attached proteins, proteins attached to the plasma membrane of one cell can interact directly with cell-surface receptors on adjacent cells. Note that some signalling molecules such as epinephrine can act in both endocrine and paracrine signalling, while other signalling molecules such as epidermal growth factor (EGF) can act by cell-cell, autocrine or paracrine signalling. Signalling By Cell-Sur
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