Overview of Cell Signaling & Transcription Regulation PDF

Molecular control of cell function and the process of development: 1. Extracellular signals: Cell surface receptors and their ligands (e.g. growth factors) mediate signal transduction in cells. 2. Transcription factors: Regulate gene expression to specify different cells...

Molecular control of cell function and the process of development: 1. Extracellular signals: Cell surface receptors and their ligands (e.g. growth factors) mediate signal transduction in cells. 2. Transcription factors: Regulate gene expression to specify different cells and to control cellular functions. (In early development: maternal transcription factors act, and at later stages under control of extracellular signals). 3. Induction: Mechanism whereby one cell population influences the development of neighbouring cells (cell and tissue differentiation). http://www.ncbi.nlm.nih.gov/books/NBK26822/ Cells in multi-cellular organism communicate and carry out functions mainly by responding to: 1) Extra-cellular signaling molecules. 2) Signals derived from cell-cell contact. Most cells emit and receive signals. (uni-cellular organisms (bacteria and yeast) also respond to extracellular signals)  Each Cell Is Programmed to Respond to Specific Combinations of Extracellular Signals Individual cell often requires multiple signal to survive, and additional ones to grow and divide, and different ones again to differentiate. Loss of signals can lead to cell death (apoptosis) Extracellular Signals Can Act Over Short or Long Distances Extracellular Signal Molecules Bind to Specific Receptors There Are Three Major Classes of Cell-Surface Receptor Proteins Signalling by extra-cellular molecules Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008) Intracellular Signaling Complexes Form at Activated Receptors Specific and precise relay of signals in a crowded cytoplasm The Speed of a Response Depends on the Turnover of Signaling Molecules -Positive and negative feedback -Control by protein alteration and degradation Cells Can Adjust Their Sensitivity to a Signal Protein trafficking, phosphorylation and ubiquitination Activated Receptor Tyrosine Kinases (RTKs) phosphorylate themselves and bind to SH2 domain containing proteins Receptor Tyrosine Kinase Families and their Ligands Trenker R, Jura N. Receptor tyrosine kinase activation: From the ligand perspective. Curr Opin Cell Biol. 2020 Apr;63:174-185. doi: 10.1016/j.ceb.2020.01.016  Spatial and Temporal Receptor Tyrosine Kinase Signalling How are specific and precise signals relayed in a crowded cytoplasm? Liquid-liquid phase separation (LLPS) at plasma membrane -LLPS: condensation of macromolecules into phase-separated membrane-less droplets -Weak, transient protein-protein interactions e.g. phosphotyrosine with an SH2 domain Signal 1.RTK: Ligand binds 2. Autophosphorylation on Tyrosines 3. Charge interaction with plasma membrane https://animationlab.utah.edu/phase-separation 4. Recruitment of signaling proteins 5. LLPS droplet forms at plasma membrane Ladbury JE, Lin CC, Suen KM. Phase separation enhances probability of receptor signalling and drug targeting. Trends Biochem Sci. 2023 May;48(5):428-436. doi: 6. Different proteins participate depending on cascade and cell state 10.1016/j.tibs.2023.01.005. Epub 2023 Feb 7. PMID: 36759237. 7. FGF receptor is well studied examples Wang, B., Zhang, L., Dai, T. et al. Liquid–liquid phase separation in human health and diseases. Sig Transduct Target Ther 6, 290 (2021). https://doi.org/10.1038/s41392-021- 8. Can include scaffolding proteins and client proteins 00678-1 9. Phosphatases included  Molecular Mechanisms that control cellular and tissue function and development: 1. 2.Extracellular signals: growth factors and cell surface receptors and ligands mediate signal transduction. 2. Transcription factors: regulate gene expression at different stages and in different cells to control cellular functions (early development: maternal transcription factors). 3.Induction: Mechanism whereby one cell population influences the development of neighboring cells (cellular differentiation). http://www.ncbi.nlm.nih.gov/books/NBK26822/ Early Drosophila Embryo; RNA gradients determine patterning or spatial differentiation of tissues  Each cell is programmed to respond to respond to specific combinations of extra cellular signal molecules; -becomes more complex during development from early embryo to adult. During early development: extracellular signals are provided by gradients of morphogens in embryo Different concentrations of morphogen induce expression of different sets of genes Figure 15-10 Molecular Biology of the Cell (© Garland Science 2008) Drosophila Even-skipped (Eve) Gene Eve: green Giant: red Expression in nuclei of early embryo: Bicoid and hunchback activate Eve transcription Kruppel and Giant repress Eve Induction: Differentiation One cell population influences the development of neighbouring cells (e.g. hedgehog signalling in wing)  Control of Gene Expression: All differentiated cells carry genetic information required to direct formation of a complete organism Genes are selectively expressed in cell and tissues after differentiation. Figure 7-2c Molecular Biology of the Cell (© Garland Science 2008)  Control of gene expression in cells: can occur at six steps: Figure 7-5 Molecular Biology of the Cell (© Garland Science 2008)