Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation

• Many cellular proteins are post-translationally modified by the addition of a single ubiquitin or a polyubiquitin chain. Among these are receptor tyrosine kinases (RTKs), which undergo ligand-dependent ubiquitination. The ubiquitination of RTKs has become recognized as an important signal for their endocytosis and degradation in the lysosome; however, it is not clear whether ubiquitination itself is sufficient for this process or simply participates in its regulation. The issue is further complicated by the fact that RTKs are thought to be polyubiquitinated - a modification that is linked to protein degradation by the proteasome. By contrast, monoubiquitination has been associated with diverse proteasome-independent cellular functions including intracellular protein movement. Here we show that the epidermal growth factor and platelet-derived growth factor receptors are not polyubiquitinated but rather are monoubiquitinated at multiple sites after their ligand-induced activation. By using different biochemical and molecular genetics approaches, we show that a single ubiquitin is sufficient for both receptor internalization and degradation. Thus, monoubiquitination is the principal signal responsible for the movement of RTKs from the plasma membrane to the lysosome.

Nyckelord

Animals

CHO Cells

Cell Membrane/*metabolism

Cricetinae

Cysteine Endopeptidases/metabolism

Endocytosis/*physiology

Eukaryotic Cells/*metabolism

Hela Cells

Humans

Lysosomes/metabolism

Mice

Multienzyme Complexes/metabolism

Proteasome Endopeptidase Complex

Protein Transport/physiology

Receptor Protein-Tyrosine Kinases/*metabolism

Receptor; Epidermal Growth Factor/metabolism

Receptors; Platelet-Derived Growth Factor/metabolism

Ubiquitin/*metabolism

Publikations- och innehållstyp

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