BIO 320 Chapter Notes - Chapter 15: Mitogen-Activated Protein Kinase Kinase, Ras Superfamily, Insulin Receptor Substrate
Chapter 15 Cell Signaling: Cell Signaling III (pg. 850-857)
• Signaling through enzyme-coupled receptors
o Enzyme-coupled receptors – transmembrane proteins with their ligand-binding domain
on the outer surface of the plasma membrane
▪ Has either intrinsic enzymatic ability or directly associates with an enzyme
▪ Most common class: receptor tyrosine kinases
• Activated receptor tyrosine kinases (RTKs) phosphorylate themselves
o Receptor tyrosine kinases (RTKs) – how many extracellular signal proteins act
▪ Includes many secreted and cell-surface bound proteins that control cell
behavior in developing and adult animals
▪ About 60 types in humans with 20 structural subfamilies
▪ Always activated by signal protein binding to extracellular binding domain
▪ Tyrosine side chains get phosphorylated on cytosolic side, which creates
phosphotyrosine docking sites for various intracellular signaling proteins
o For GPCR, ligand binding changes the orientation of the stiff alpha helices, which causes
a conformational change on the opposite side of the membrane
▪ Multiple helix receptors dimerize, which brings their cytoplasmic kinase
domains together
▪ Dimerization stimulates many other mechanisms
• I.e. epideral groth fator EGF is’t atiated y phosphorylatio
but by conformational change
• Phosphorylated tyrosines on RTKs are docking sites for other intracellular signaling proteins
o Once kinase domains are activated, they phosphorylate many additional sites outside
the kinase domain, which creates docking sites
o Once bound to RTK, signaling protein may become phosphorylated and activated
▪ Binding alone can causes conformational change or proximity to the next signal
protein
▪ Insulin receptor substrate 1 (IRS1) – associates with phosphorylated tyrosines
and then gets phosphorylated at multiple sites to create more docking sites
• Proteins with SH2 domains bind to phosphorylated tyrosines
o Interaction domains – mediates chains of protein-protein interactions
o Phospholipase C-gamma (PLCgamma) – functions same as phospholipase C-beta,
activates the inositol phospholipid signaling pathway
o Phosphoinositide 3-kinase (PI 3-kinase) – phosphorylates lipids instead of proteins to
make lipid docking sites
o SH2 domains and/or PTB domains– highly conserved phosphotyrosine-binding domains
▪ Enables proteins to bind to RTKs
▪ Some decrease the signaling process rather than progressing it
• I.e. c-Cbl protein catalyzes ubiquitylation
o Mutations that inactiviate c-Cbl-dependent RTK causes
prolonged RTK signaling, which can cause cancer
▪ RTKS can also be endocytosed and relay signals from inside the cell
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