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.

EGF

EGFR(inactive)

EGFR(dimerized, phospho-Y)

active

EGF

POSITIVE SIGNALING SIGNAL TERMINATION

Cbl (E3)

Several pathwaysactivated for growth

or differentiation

Internalization,ubiquitination,

trafficking to lysosome

Cbl Terminates Growth Factor Signaling Thru Receptor Ubiquination

Proteasomal Degradation Can Activate Signaling Pathways:Transcription Via NFB

UbUbUbUbUbUb

UbUbUbUbUbUb

Nuclear TransportDNA Binding

Transcription Activation

ProteasomeDegradation

NFB

IB

ExtracellularSignal

IKK E3