Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation

Kaisa Haglund, Sara Sigismund, Simona Polo, Iwona Szymkiewicz, Pier Paolo Di Fiore, Ivan Dikic

Research output: Contribution to journalArticle

610 Citations (Scopus)

Abstract

Many cellular proteins are post-translationally modified by the addition of a single ubiquitin or a polyubiquitin chain1. Among these are receptor tyrosine kinases (RTKs), which undergo ligand-dependent ubiquitination2. The ubiquitination of RTKs has become recognized as an important signal for their endocytosis and degradation in the lysosome3; 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 proteasome4. By contrast, monoubiquitination has been associated with diverse proteasome-independent cellular functions including intracellular protein movement5. 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.

Original languageEnglish
Pages (from-to)461-466
Number of pages6
JournalNature Cell Biology
Volume5
Issue number5
DOIs
Publication statusPublished - May 1 2003

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Receptor Protein-Tyrosine Kinases
Endocytosis
Ubiquitination
Ubiquitin
Molecular Biology
Polyubiquitin
Ligands
Platelet-Derived Growth Factor Receptors
Proteasome Endopeptidase Complex
Lysosomes
Epidermal Growth Factor
Proteolysis
Proteins
Cell Membrane

ASJC Scopus subject areas

  • Cell Biology

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Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. / Haglund, Kaisa; Sigismund, Sara; Polo, Simona; Szymkiewicz, Iwona; Di Fiore, Pier Paolo; Dikic, Ivan.

In: Nature Cell Biology, Vol. 5, No. 5, 01.05.2003, p. 461-466.

Research output: Contribution to journalArticle

Haglund, K, Sigismund, S, Polo, S, Szymkiewicz, I, Di Fiore, PP & Dikic, I 2003, 'Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation', Nature Cell Biology, vol. 5, no. 5, pp. 461-466. https://doi.org/10.1038/ncb983
Haglund, Kaisa ; Sigismund, Sara ; Polo, Simona ; Szymkiewicz, Iwona ; Di Fiore, Pier Paolo ; Dikic, Ivan. / Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. In: Nature Cell Biology. 2003 ; Vol. 5, No. 5. pp. 461-466.
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