Regulated Proteolysis Notes

Regulated Proteolysis Notes =========================== Notch Signaling --------------- in development, the pathway controls cell fate by amplifying molecular differences between adjacent cells\ lateral inhibition is a process via which isolated single cells in a population of precursor/identi...

Regulated Proteolysis Notes =========================== Notch Signaling --------------- in development, the pathway controls cell fate by amplifying molecular differences between adjacent cells\ lateral inhibition is a process via which isolated single cells in a population of precursor/identical cells commit to a fate;\ these "specialized" cells inhibit their neighbors from acquiring the fate\ lateral inhibition is achieved by the binding of ligand Delta (or other Delta-like ligands) to Notch receptor on neighboring\ cells to inhibit differentiation\ in some tissues, Notch signaling works in the opposite way, causing neighboring cells to behave similarly\ \ Notch and Delta are single-pass transmembrane proteins\ activated by Delta on an adjacent cell, an intracellular protease cleaves the cytoplasmic domain of Notch; the released\ domain moves to the nucleus to activate gene transcription\ in the nucleus, the intracellular Notch domain binds CSL converting it from a transcriptional repressor to an activator\ after its synthesis, Notch is cleaved into two domains that re-assemble to a heterodimer (the mature receptor); the binding\ of Delta to Notch induces the second cleavage in the extracellular domain, and a third cleavage releases the intracellular\ Notch domain (see above) Wnt Signaling ------------- the controlled proteolysis of beta-catenin is essential for the control of canonical Wnt signaling\ Wnt signaling is essential for stem cell maintenance in the intestine and controls cell fate\ Wnt signaling deregulated in most cases of colorectal cancer\ \ Wnt proteins: secreted local mediators; Frizzled: Wnt receptors\ the pathway controls the localization of beta-catenin; usually located at adherens junctions; the "free" cytosolic beta-catenin\ is maintained at low levels through degradation\ glycogen synthase kinase-3b phosphorylates cytosolic beta-catenin, targeting it for degradation; adenomatous polyposis coli\ (APC) promotes the degradation by mediating the association of the degradation complex with beta-catenin\ binding of Wnts to Frizzled and a co-receptor (LRP) inhibits beta-catenin degradation through Dishevelled and a serine/threonine\ kinase casein kinase 1; beta-catenin accumulates in the cytoplasm and nucleus\ in the nucleus, beta-catenin binds DNA-binding proteins LEF-1/TCF and induces genes that support cell growth and proliferation Hedgehog Signaling ------------------ Hedgehog Signaling\ Molecular Biology of the Cell. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science\ \ Hedgehog ligands: secreted local mediators\ active Hedgehog proteins are covalently coupled to cholesterol, which restricts their diffusion\ Patched and Smoothened are the transmembrane receptors; in the absence of a Hedgehog signal, Patched inhibits\ the activity of Smoothened\ binding of Hedgehog to Patched allows Smoothened to relay the signal into the cell\ in the absence of Hedgehog, a gene regulatory protein Ci is processed to a smaller protein that accumulates in the nucleus,\ where it acts as a transcriptional repressor\ the proteolytic processing of the Ci protein depends on a complex\ when Hedgehog binds to Patched, unprocessed Ci protein is released from its complex and enters the nucleus, where it\ activates the transcription of Hedgehog target genes NF-κB Signaling --------------- NF-κB proteins (homo- or heterodimers of RelA, RelB, c-Rel, NF-κB1, NF-κB2) are latent gene regulatory proteins, usually\ inactive in the cytoplasm\ in response to inflammation, active NF-κB turns on gene transcription\ IκB binds NF-κB proteins to inactive these in cytoplasmic complexes\ cytokines (TNF-α, IL-1) bind their receptors, trigger the phosphorylation/degradation of IκB\ IκB is phosphorylated by the serine/threonine kinase IκB kinase (IKK)\ the degradation of IkB exposes a nuclear localization signal on the NF-kB proteins allowing for nuclear localization\ some proteins recruited to the TNF-α receptor contribute to the MAP-kinase cascade or lead to apoptosis New Perspectives ---------------- New Perspectives\ The ability to transduce a signal across a membrane remains only poorly understood.\ Recently, a new mechanism of transduction across a membrane has been described.\ In this model, proteases embedded within the membrane are triggered to catalyze the proteolytic release of\ membrane-anchored transcription factors.\ These novel proteases are polytopic membrane proteins with catalytic sites embedded in the lipid bilayer. Putting It Together ------------------- Putting It Together\ Notch receptors are activated by cleavage when bound by a ligand on the neighboring cell; the intracellular Notch domain\ enters the nucleus to stimulate gene transcription\ in Wnt signaling, the proteolysis of beta-catenin is inhibited when Wnt ligands bind to their receptors; beta-catenin enters\ the nucleus and activates gene transcription\ in Hedgehog signaling, in the absence of ligands, cytoplasmic gene regulatory protein Ci is cleaved to form a transcriptional\ repressor; in the presence of ligands, the larger form of Ci activates gene transcription\ NF-κB is inactivated by inhibitory protein IκB in a complex in the cytoplasm; proinflammatory cytokines trigger a phosphorylation\ cascade that ultimately phosphorylates IκB, marking it for degradation; this enables the freed NF-κB to enter the nucleus and\ activate gene transcription