Cell Signaling
Lecture 13 and 14
Ligand-activated Notch undergoes 2 cleavages
before releasing the transcription factor
ADAM10: A
disintegrin
and
Metalloprote
ase
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.
Wnt Signals trigger release of a transcription from
cytosolic protein complex
1. In the absence of Wnt (protooncogene: a normal cellular gene
whose inappropriate expression
promotesthe onset of cancer), Bcatenin is found in a complex with
Axin, APC and the kinase GSK3.
2. The kinase GSK3 phosphorylates Bcatenin leading to its degradation.
3. The TCF transcription factor in the
nucleus acts as a repressor of target
genes unless altered by Wnt
signaling.
1. Binding of Wnt to its receptor
Frizzled (Fz) triggers
phosphorylation of the LRP coreceptor by GSK3 and another and
another kinase, and thus allows
subsequent binding of Axin.
2. This disrupts the Axin-APC-GSK3B-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
Processing of Hh
Hedgehog Signaling