LECT 21: REGULATED PROTEIN TURNOVER
Cellular proteins have different stabilities. It is the combination of
synthesis and degradation rates that determines the level of a protein
in a cell, and changes in either rate can serve as means to regulate
a protein’s concentration in the cell.
Protein degradation in response to extracellular signals is an important
component of some intracellular signaling pathways.
Protein degradation is further required to mis-folded or de-folded proteins,
which would otherwise be capable of forming insoluble aggregates.
Machinery for Protein Degradation Within Cells
Cytosolic proteins targeted for degradation are digested in the
26S proteasome, a large multienzymatic structure.
Membrane proteins targeted for degradation travel through endosomes
to the lysosome, whose lumen contains a collection of proteases.
Both targeting processes employ the covalent
tagging of proteins with ubiquitin,
a small 76 amino acid polypeptide.
Cbl Terminates Growth Factor Signaling Thru Receptor Ubiquination
EGF
EGF
EGFR
(inactive)
POSITIVE SIGNALING
EGFR
(dimerized, phospho-Y)
active
SIGNAL TERMINATION
Cbl (E3)
Several pathways
activated for growth
or differentiation
Internalization,
ubiquitination,
trafficking to lysosome
Proteasomal Degradation Can Activate Signaling Pathways:
Transcription Via NFkB
Extracellular
Signal
Proteasome
Degradation
IkB
IKK
E3
Ub
Ub
Ub
NFkB
Nuclear Transport
DNA Binding
Transcription Activation
Ub
Ub
Ub