3) Cell Receptors, Ola Elgaddar

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The third lecture about the "Cell". …

The third lecture about the "Cell".
Here, I am giving a quick view about different types of receptors and their mechanism of action.

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  • 1. LAB EVALUATION OF CELL DISORDERS 3) Receptors Ola H. Elgaddar MD, PhD, CPHQ, LSSGB Lecturer of Chemical Pathology Medical Research Institute Alexandria University Ola.elgaddar@alexu.edu.eg
  • 2. Signal Transduction Systems: -Signal transduction is the chemistry that allows communication at the cellular level. - Cells sense signals from the extracellular and intracellular environments, as well as directly from other cells.
  • 3. - Cells respond to these signals in a variety of ways, primarily by modifying protein levels, activities, and location. - Protein levels are controlled by rates of transcription, translation, and proteolysis, whereas protein activities are affected by covalent modifications and non-covalent interactions with other proteins and small molecules.
  • 4. - Most signals are initiated by ligands and are sensed by the receptors to which they bind. - Binding of a ligand to a receptor stimulates the activities of proteins necessary to continue the transmission of the signal through the formation of multi-protein complexes and the generation of small-molecule second messengers. - Integration of signals from multiple pathways determines the cell's ultimate response to competing and complementary signals.
  • 5. Signals (Ligands): -Signal transduction pathways respond to different types of stimuli. - Molecules that initiate signaling cascades include proteins, amino acids, lipids, nucleotides, gases, and light.
  • 6. Several classifications for signals! - Some signals are continuous, such as those sent by the extracellular matrix, whereas others are episodic, like the secretion of insulin by pancreatic cells in response to increases in blood glucose.
  • 7. - Signaling molecules originate from a variety of sources. Some, such as neurotransmitters, are stored in the cell and are released to provide communication with other cells under specific conditions. Other ligands are stored outside the cell (e.g., in the extracellular matrix) and become accessible in response to tissue damage or remodeling.
  • 8. - Traditionally, signals have been divided based on the cell of origin into those that affect distant cells (endocrine), nearby cells (paracrine), or the same cell (autocrine).
  • 9. Receptors: -The plasma membrane of eukaryotic cells serves to insulate the cell from the outside environment, but this barrier must be breached to transmit signals of extracellular origin. - This fundamental problem of transmitting extracellular signals is solved in two ways:
  • 10. 1. Signals cross the plasma membrane by activating transmembrane receptors
  • 11. 2. Using ligands that are membrane permeable
  • 12. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 13. 1) Receptor Tyrosine Kinases -Receptor tyrosine kinases are transmembrane proteins that have an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. - The ligands for these receptors are proteins or peptides
  • 14. - Most receptor tyrosine kinases are monomeric, but members of the insulin-receptor family are heterotetrameres in which the subunits are linked by disulfide bonds. - Examples of tyrosine kinase receptors include the insulin receptor, the platelet-derived growth factor (PDGF) receptor, the EGF receptor family, and the fibroblast growth factor (FGF) receptor family.
  • 15. - Activation of receptor tyrosine kinases generally requires tyrosine phosphorylation of the receptor. In the case of the insulin receptor, an insulin- stimulated conformational change activates the kinase. Most other tyrosine kinases are activated by ligand-induced oligomerization, which brings the kinase domains of distinct molecules into close proximity so that they cross-phosphorylate.
  • 16. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 17. 2) Serine-Threonine Kinase Receptors -The TGF-β receptors are transmembrane proteins with intrinsic serine-threonine kinase activity. - There are two types; type I & II - TGF-β ligands are dimers that bind to and oligomerize type I and type II receptors.
  • 18. - The type II receptors seem to be constitutively active but do not normally phosphorylate substrates, whereas the type I receptors are normally inactive - Ligand-mediated dimerization of the type I and type II receptors causes the type II receptor to phosphorylate the type I receptor
  • 19. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 20. 3) Receptor Phosphotyrosine Phosphatases - Protein tyrosine phosphatases (PTPs) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. - They have an extracellular domain, a single transmembrane-spanning domain, and cytoplasmic catalytic domains.
  • 21. -The extracellular domains of some receptor tyrosine phosphatases contain fibronectin and immunoglobulin repeats, suggesting that these receptors may recognize adhesion molecules as ligands.
  • 22. - Functional and structural evidence suggests that the phosphatase activity of some of these receptors is inhibited by dimerization - Ligand-dependent dimerization could cause constitutively active tyrosine phosphatases to lose activity, enhancing signals emanating from tyrosine kinases. - These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation and differentiation
  • 23. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 24. 4) G protein-coupled receptors (GPCRs) -GPCRs are by far the most numerous receptors as they encode the light, smell, and taste receptors. -Examples include thrombin, neurotransmitters and EGF receptors. - Structurally GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus
  • 25. - Intramolecular bonds involving residues in the transmembrane or juxtamembrane regions keep GPCRs in an inactive conformation. - In the inactive state, the receptor is bound to a heterotrimeric G protein, which is also inactive. - Agonist binding causes a conformational change that stimulates the guanine nucleotide exchange activity of the receptor. Exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the heterotrimeric G proteins initiates signaling.
  • 26. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 27. 5) Notch Family of Receptors - The Notch receptor has a large extracellular domain, a single transmembrane domain, and a cytoplasmic domain. -Ligands for the Notch receptor are proteins expressed on the surface of adjacent cells, and activation results in two proteolytic cleavages of Notch, releasing its cytoplasmic region as a soluble signal - This fragment moves to the nucleus, where it complexes with a transcriptional repressor, relieving its inhibitory effects and stimulating transcription
  • 28. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 29. 6) Guanylate Cyclases - Guanylate cyclases (GCs) convert GTP to cGMP upon activation. There are two forms of GCs: Membrane GCs are receptors for atrial natriuretic hormone, peptides that regulate intestinal secretion and are necessary for regulating cGMP levels for vision. Soluble GCs are activated by nitrous oxide. These receptors are widely expressed and regulate vascular tone and neuron function.
  • 30. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 31. 7) Tumor Necrosis Factor Receptor Family - The TNF family of receptors has a cysteine-rich extracellular domain, a transmembrane domain, and a death domain in the cytoplasm -Receptors undergo oligomerization after ligand binding - Stimulation of the receptor leads to recruitment of cytoplasmic proteins that bind to each other and the receptor through death domains, thereby activating a protease, caspase 8 that initiates apoptosis - Under some conditions, however, TNFRs may stimulate antiapoptotic signals
  • 32. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 33. 8) WNT Receptors -The wnt family of growth and differentiation factors consists of small proteins that bind to cell surface receptors of the Frizzled family -These receptors resemble GPCRs but utilize a unique mechanism of signal transduction. - Wnt proteins got their name from two of the first to be discovered: Wingless (wg) in Drosophila and its homolog Int-1 in mice
  • 34. - Binding of wnt to the receptor suppresses a kinase cascade complex that involves many proteins. - This complex mediates phosphorylation and ultimately proteosome-depend degradation of β- catenin - Suppression of β-catenin degradation in response to wnt allows β-catenin to accumulate in the cell and to migrate into the nucleus where it regulates genes involved in cell growth regulation
  • 35. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 36. 9) Nuclear Receptors -Ligands for nuclear receptors diffuse into the cell and bind their receptors on the nucleus. - The ligands include steroids, eicosanoids, retinoids, and thyroid hormone.
  • 37. - The receptors are transcription factors that have both DNA- and ligand-binding domains. -The unliganded receptor is bound to heat-shock proteins that are dissociated after ligand binding. -Release from the chaperone complex and ligand association lead to binding of the receptor to cofactors and DNA to regulate transcription.
  • 38. Chaperones are proteins that assist the non-covalent folding or unfolding and the assembly or disassembly of other macromolecular structures, but do not occur in these structures when the structures are performing their normal biological functions
  • 39. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 40. 10) Adhesion Receptors - Cell adherence, either to the extracellular matrix or to other cells, is mediated by receptors that function mechanically and stimulate intracellular signaling pathways, primarily through tyrosine kinases - Integrins mediate adherence to extracellular matrix and are composed of heterodimers of α and β subunits. - There is a ligand-binding site that binds the extracellular matrix and a cytosolic domain that binds the cytoskeleton.
  • 41. - Interaction between the extracellular domain of integrins and an extracellular ligand generate a variety of signals. - The interaction leads to clustering of integrins and the rapid tyrosine phosphorylation of proteins at the cytoplasmic face. - Focal adhesion kinase (FAK) is an effector in integrin-mediated responses.
  • 42. Receptors in Signal Transduction: 1) Receptor Tyrosine Kinases 2) Serine-Threonine Kinase Receptors 3) Receptor Phosphotyrosine Phosphatases 4) G protein-coupled receptors 5) Notch Family of Receptors 6) Guanylate Cyclases 7) Tumor Necrosis Factor Receptor Family 8) WNT Receptors 9) Nuclear Receptors 10)Adhesion Receptors
  • 43. SIGNALING!!