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Cell SignalingLecture 13 and 14
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Ligand-activated Notch undergoes 2 cleavages before releasing the transcription factor
ADAM10: A disintegrin and Metalloprotease
1. Notch is cleaved by the matrix metalloprotease ADAM10, which is bound to the membrane releasing the extracellular Notch segment
2. Y-secretase, a complex of four membrane proteins including the protease presenilin 1 (PS1) then associates with the remaining portion of Notch
3. and catalyzes an intramembrane cleavage that releases the cytosolic segment of Notch.
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Wnt Signals trigger release of a transcription from cytosolic protein complex
1. In the absence of Wnt (proto-oncogene: a normal cellular gene whose inappropriate expression promotesthe onset of cancer), B-catenin is found in a complex with Axin, APC and the kinase GSK3.
2. The kinase GSK3 phosphorylates B-catenin leading to its degradation.
3. The TCF transcription factor in the nucleus acts as a repressor of target genes unless altered by Wnt signaling.
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1. Binding of Wnt to its receptor Frizzled (Fz) triggers phosphorylation of the LRP co-receptor by GSK3 and another and another kinase, and thus allows subsequent binding of Axin.
2. This disrupts the Axin-APC-GSK3-B-catenin complex, preventing phosphorylation of B-catenin by GSK3 which leads accumulation of B-catenin in the cell.
3. After translocation to the nucleus, B-catenin may act with TCF to activate target genes or, alternately cause the export of TCF from the nucleus and possibly its activation in the cytosol
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Processing of Hh
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Hedgehog Signaling
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