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PMID: 20573067 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

γ-secretase-dependent cleavage initiates notch signaling from the plasma membrane.

Traffic (Copenhagen, Denmark) ·Vol. 11 ·No. 9 ·2010-09-00 ·Pages 1234-45

Sorensen EB, Conner SD

Abstract

Notch signaling is critical to animal development, and its dysregulation leads to human maladies ranging from birth defects to cancer. Although endocytosis is currently thought to promote signal activation by delivering activated Notch to endosome-localized gamma-secretase, the data are controversial and the mechanisms that control Notch endocytosis remain poorly defined. Here, we investigated the relationship between Notch internalization and signaling. siRNA-mediated depletion studies reveal that Notch endocytosis is clathrin-dependent and requires epsin1, the adaptor protein complex (AP2) and Nedd4. Moreover, we show that epsin1 interaction with Notch is ubiquitin-dependent. Contrary to the current model, we show that internalization defects lead to elevated gamma-secretase-mediated Notch processing and downstream signaling. These results indicate that signal activation occurs independently of Notch endocytosis and that gamma-secretase cleaves Notch at the plasma membrane. These observations support a model where endocytosis serves to downregulate Notch in signal-receiving cells.

MeSH Terms
Adaptor Proteins, Vesicular Transport/metabolism Amyloid Precursor Protein Secretases/chemistry,metabolism Cell Membrane/metabolism Endosomal Sorting Complexes Required for Transport/metabolism Endosomes/chemistry HeLa Cells Humans Nedd4 Ubiquitin Protein Ligases Receptors, Notch/metabolism Signal Transduction Ubiquitin/metabolism Ubiquitin-Protein Ligases/metabolism
Chemicals
Adaptor Proteins, Vesicular Transport Endosomal Sorting Complexes Required for Transport Receptors, Notch Ubiquitin Nedd4 Ubiquitin Protein Ligases Nedd4 protein, human Ubiquitin-Protein Ligases Amyloid Precursor Protein Secretases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Sorensen Erika B
Department of Genetics, Cell Biology, and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Conner Sean D
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Article Info
Journal
Traffic (Copenhagen, Denmark)
Abbr.
Traffic
ISSN
1600-0854
DOI
10.1111/j.1600-0854.2010.01090.x
Published
2010-09-00
Epub
2010-00-21
Pages
1234-45
Language
English
Region
England
NLM ID
100939340
PMCID
PMC2919600
Subset
IM
Grants
NIGMS NIH HHS · R01 GM085029 · United States
NICHD NIH HHS · T32 HD007480 · United States
NIGMS NIH HHS · R01 GM085029-02 · United States
NIGMS NIH HHS · GM085029 · United States
NICHD NIH HHS · 2T32-HD007480-11A1 · United States
External Links
PubMed source DOI: 10.1111/j.1600-0854.2010.01090.x PMC Full Text View journal details
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