Sustaining Proliferative Signaling and Evading Growth Suppressors Oct 17 2017

Hallmarks of Cancer, 2011

Communication in Simple cells Quorum sensing in bacteria resulting in motility, antibiotic production, spore formation, or conjugation

Signaling Molecules Molecule Types: Proteins, Small peptides, and amino acids Nucleotides Retinoids and Fatty acid derivatives Dissolved gases, nitric oxide and carbon monoxide Molecule Activation: Released through exocytosis Diffusion Displayed on the external cell surface Release of transmembrane proteins via cleavage

Extracellular Signal Molecule Binding Hydrophilic molecules bind at the cell surface Hydrophobic and small molecules mass bind in the cell interior

Forms of Intercellular Signaling Autocrine – a cell responding to a signal that they produce

Endocrine vs. Neuronal Strategies Fast and high concentrations Slow and low concentrations

Extracellular Signals Protein Modification can be fast Gene Expression can be slow

Signal Sharing Water-soluble (hydrophilic) Molecules Gap Junctions are short cytoplasmic bridges Communication is bidirectional

Multiple Extracellular Signals Cells display a particular set of receptors that responds to another set of signal molecules Different combinations will result in different functions

Same Signal – Different Result Same signal and same receptor Differences in intracellular signaling proteins activated Extracellular signal has no information

Signal Gradients Development Different Level of Receptor Activation lead to different concentrations of regulatory proteins and therefore different gene expression High Signal Concentration, One Effect Low Signal Concentration, Different Effect

Protein Turnover Decrease in Synthesis Results in Degradation Blue = molecule half life Applies to proteins within or outside the cell

Protein Turnover Increase in Synthesis New molecules being produced Blue = molecule half life Another method is conversion of molecules from an inactive to active state

Extracellular Signal Molecule Binding Hydrophilic molecules bind at the cell surface Hydrophobic and small molecules mass bind in the cell interior

Intracellular Receptors Nitric Oxide -Produced by Nitric oxide synthase -Involved in relaxation of smooth muscle

Nitric Oxide -Synthesized from deamination of arginine -Rapidly diffuses out and into cells to act locally -Very short half life, 5-10 seconds -Reversibly binds to the active site of guanylyl cyclase to produce cyclic GMP -Guanylyl cyclase acts as both the intracellular receptor and as the intracellular signaling protein -Phophodiesterase rapidly degrades cGMP back to GMP

Nitric Oxide Synthases (NOS) Types: eNOS – epithelial NOS -activated by calcium and phosphorylation nNOS – nerve and muscle NOS -constitutively make NOS -activated by calcium influx iNOS – macrophages -inducible NOS -only made when the cell is activated in response to infection

Hydrophobic Signal Molecules -Diffuse across the plasma membrane -Bind to intracellular receptor proteins that can then bind to DNA to regulate transcription of specific genes

Nuclear Receptor Superfamily Serve 2 functions: -Intracellular Receptors -Intracellular Effectors -48 human nuclear receptors -The binding ligand is not known for half of them

Inactive Receptors -Found in either the cytosol or the Nucleus -Inhibitory proteins are typically bound to prevent unwanted transcription

Active Receptors -Ligand binding alters receptor shape and allows binding of additional activator proteins -They bind as homodimers or heterodimers

Conformational Change The change in receptor shape causes DNA binding resulting in either transcription activation or repression Translocation to the Nucleus!!!

Hormone Response Negative Feedback 30 minutes Other gene regulatory proteins are required to combine with the activated receptor to regulate transcription

Classes of Cell-Surface Receptors -Most molecules bind receptors on the target cell surface and do not enter the cell -Receptors act as a signal transducer 3 Largest Classes: Ion-Channel-Coupled Receptor G-Protein-Coupled Receptor Enzyme-Coupled Receptor

Ion-Channel-Coupled Receptors aka transmitter-gated ion channels Rapid synaptic signaling between nerve cells, and nerve and muscle cells Neurotransmitters open and close the ion channels

G-Protein-Coupled Receptors G-Proteins (Trimeric GTP-binding protein) act as an intermediate between the receptor and target protein Target proteins are enzymes or ion channel G-Protein Receptors are multipass transmembrane proteins

Enzyme-Coupled Receptors Function in 2 ways: Directly as enzymes Associate with enzymes they activate Typically single-pass transmembrane proteins Heterogeneous in their structure, but many have kinases activity

Intracellular Signaling Small intracellular mediators or second messengers -Generated in large numbers after ligand/receptor binding -Diffuse away from their source to spread their signal -They pass the signal to selected signaling proteins or effector proteins

Signal Transduction