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Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of melanocytes.
Sci. Signal. 10:eaai8288 (2017)
The evolution of cancer is characterized by the appearance of specific mutations, but these mutations are translated into proteins that must cooperate to induce malignant transformation. Using a systemic approach with the multiepitope ligand cartography (MELC) technology, we analyzed protein expression profiles (PEPs) in nevi and BRAF(V600E)-positive superficial spreading melanomas (SSMs) from patient tissues to identify key transformation events. The PEPs in nevi and SSMs differed predominantly in the abundance of specific antigens, but the PEPs of nevi- and melanoma-associated keratinocytes gradually changed during the transformation process. A stepwise change in PEP with similar properties occurred in keratinocytes cocultured with melanoma cells. Analysis of the individual steps indicated that activation of the metalloproteinase ADAM10 by signal peptide peptidase-like 3 (SPPL3) triggered by mutant BRAF(V600E) was a critical transformation event. SPPL3-mediated ADAM10 activation involved the translocation of SPPL3 and ADAM10 into Rab4- or Rab27-positive endosomal compartments. This endosomal translocation, and hence ADAM10 activation, was inhibited by the presence of the tumor suppressor PTEN. Our findings suggest that systematic tissue antigen analysis could complement whole-genome approaches to provide more insight into cancer development.
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Publication type
Article: Journal article
Document type
Scientific Article
Language
english
Publication Year
2017
HGF-reported in Year
2017
ISSN (print) / ISBN
1945-0877
e-ISSN
1937-9145
Journal
Science Signaling
Quellenangaben
Volume: 10,
Issue: 470,
Article Number: eaai8288
Publisher
American Association for the Advancement of Science (AAAS)
Reviewing status
Peer reviewed
Institute(s)
Institute of Molecular Immunology (IMI)
POF-Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s)
Immune Response and Infection
PSP Element(s)
G-501793-001
WOS ID
WOS:000397718800005
Scopus ID
85016310340
PubMed ID
28292959
Erfassungsdatum
2017-06-13