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Cell Signalling.docx

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Western University
Biology 2382B
Jessica Kelly

Lecture 15 – Cell Signalling Signal Transduction Signal Transduction - taking one cellular signal and converting it into another signal • External signals  external molecules/stimuli (light, neurotransmitters, GF’s, , cytokines, etc…) • Signal transduction plays very important roles in development and physiology of an organism • Disruptions in normal function can result in a host of diseases and conditions including diabetes, heart disease, & cancer • Complex mechanisms that have only recently been begun to be understood (began to be researched heavily in 70’s and 80’s) Phosphorylation found to play a large role in many of these pathways… Examples of Some of The Players:  G-protein Coupled Receptors (GPCR’s)  Receptor Tyrosine Kinases (RTK’s)  Proto-oncogenes (Ras)  Mitogen Activated Protein Kinases (MAPK) 1 Basic Elements of Cell Signaling No cells live in isolation thus they must be able to communicate with one another as well as receive & respond to signals from their environment (even single-celled organism communicate)…this is mediated main by extracellular signaling molecules… (heat, light, other physical signals are also used)… • Signal or Signaling molecule (ligand, primary messenger) o Small molecules  epinephrine, acetylcholine, steroids, peptides, hormones, etc… o Large molecules  growth factors, cytokines (proteins), etc… • Receptors  for signaling molecules o Cell-surface receptors - o Intracellular receptors • Intracellular Signaling and Effector Proteins o Perform the function of transmitting the signal inside of the cell (i.e. G proteins, protein kinases and phosphatases, etc…) • Second messengers  usually small molecule or ions involved in amplifying the signal/aid in transmission 2+ o Ca , cAMP, cGMP, IP3, DAG, NO, etc. 2 Binding At Cell Surface or Intracellular Cell-surface receptors  transmembrane proteins that contain both an extracellular and cytosolic domain • They bind hydrophilic signaling molecules that can freely diffuse in the extracellular space but cannot pass through the PM (due to hydrophilic nature) • Mechanism must be available to transduce the signal from this molecule from the cell surface to the inside of the cell • Carrier proteins must be used to transport small hydrophobic signaling molecules to the PM (can’t freely diffuse through hydrophilic extracellular space) where they can diffuse into the cell and directly transfer their sign(able to cross PM due to hydrophobic nature) 3 Nuclear-Receptor Superfamily • Nuclear receptor superfamily proteins have a common domain that can bind the ligand or theses steroid hormones • Nuclear receptor superfamily members can be in the nucleus or cytoplasm but perform their function in the nucleus by binding to DNA (transcription factors) Lipid-soluble hormones bind to intracellular receptors which constitute the nuclear- receptor superfamily of transcription factors… • Steroid hormones are synthesized by adrenal glands (an endocrine gland which sits on the top of the kidney) • Steroid hormones (derived from cholesterol) are often the molecules that are small hydrophobic signals that can cross the PM 4 Gene Activation By A Nuclear Receptor In general… Response elements - characteristic nucleotide sequences of the DNA sites that bind nuclear receptors Absence of hormone (ligand)  receptor is trapped in the cytoplasm by inhibitor proteins that bind to it (e.g. HSP90) Hormone (ligand) binding  releases the inhibitory protein which allows the receptor to enter the nucleus • Receptor binds to a response element of the target gene and stimulates formation of the pre-initiation complex assembly required for transcription (mRNA synthesis) 5 Example: Glucocorticoid Receptor Glucocorticoid - a potent anti-inflammatory and immunosuppressive hormone…also has many other functions • Glucocorticoid receptor found in cytoplasm in inactive state when not bound to steroid hormone ligand In presence of glucocorticoid  activated and moves into the nucleus (nuclear translocation) and dimerizes to form a homodimer • Homodimer can then bind to the response element sequence of DNA Net effect = opening up of DNA by recruiting a variety of other proteins  this makes DNA more available to transcription and increases gene expression… 6 Basic Concepts of Signal Transduction • Hydrophilic ligand cannot cross PM must bind to transmembrane receptor protein • Binding of ligand  causes a conformational change in the receptor proteins cytosolic domain • Intracellular signaling proteins or molecules act as secondary messengers to transduce the signal from the receptor protein to effector proteins • These effector proteins can perform a function in response to the extracellular signal and can be involved in a variety of different functions 7 Four Forms of Intercellular (between cells) Signaling 1. Endocrine  signalling molecules synthesized & secreted by signalling cells (endocrine cells) and signal molecules travel to distant target cells through the circulatory system. The term hormone generally refers to signalling molecules that mediate endocrine signalling. endo = within 2. Paracrine  signal is transmitted to nearby cells or adjacent cells (i.e. the signalling molecules released by a signal cell affect only those target cells in close proximity (e.g. neurotransmitters) para = means adjacent 3. Autocrine  signal is produced by a cell who’s target is the same cell itself (i.e. cells respond to substances that they themselves release) Target sites on same cells 4. Membrane-Attached Signaling  extracellular signal is attached to the membrane of the signaling cell and interacts with a transmembrane receptor on the surface of an adjacent target cell. Works transmembranally. 8 Where is the ligand produced and where does it perform its signalling function? Signalling By Cell-Surface Receptors 1/2  Synthesis and release the signaling molecule by the signaling cell 3/4  Transport and binding the signal to a specific receptor of the target cell (change in the conformation!) 5  Initiation of one or more intracellular signal-transduction pathways 6a  Short-term cellular responses (protein modification/interactions) 6b  Long-term cellular responses (changes in gene expression) 7/8  Termination of cellular response Signal Transduction - overall process of converting extracellular signals into intracellular responses, as well as the individual steps of the process • Termination of the cellular response is caused by intracellular signaling molecules that inhibit receptor function and by removal of the extracellular signal Short-Term Cellular Responses - associated with changes in the activity and functions of specific enzymes and other proteins that pre-exist in the cell Long-Term Cellular Responses - associated with changes in the amounts of specific proteins produced by a cell, most commonly by modification of transcription factors that stimulate or repress gene expression • Want to be able to turn a signal off (autofeedback achieves this)  can occur in a number of different ways 9 Signals Can Act Slowly & Rapidly To Induce A Response Fast Response (
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