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.
Haglund
Kaisa
K
Ludwig Institute for Cancer Research, Husargatan 3, SE-75 124 Uppsala, Sweden.
Sigismund
Sara
S
Polo
Simona
S
Szymkiewicz
Iwona
I
Di Fiore
Pier Paolo
PP
Dikic
Ivan
I
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D005057:Eukaryotic Cells / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D021381:Protein Transport / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
D009097:Multienzyme Complexes; D025801:Ubiquitin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex