SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2

Cécile Naudin, Audrey Sirvent, Cédric Leroy, Romain Larive, Valérie Simon, Julie Pannequin, Jean-François Bourgaux, Josiane Pierre, Bruno Robert, Frédéric Hollande and Serge Roche ()
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Cécile Naudin: CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2
Audrey Sirvent: CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2
Cédric Leroy: CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2
Romain Larive: CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2
Valérie Simon: CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2
Julie Pannequin: CNRS UMR5203, INSERM U661, Institut de Génomique Fonctionnelle, University of Montpellier 1 and 2
Jean-François Bourgaux: CHU Carémeau
Josiane Pierre: INSERM U749, Institut Gustave Roussy
Bruno Robert: INSERM U896, Institut de Recherche en Cancérologie de Montpellier, University of Montpellier 1 and 2
Frédéric Hollande: CNRS UMR5203, INSERM U661, Institut de Génomique Fonctionnelle, University of Montpellier 1 and 2
Serge Roche: CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract The adaptor SLAP is a negative regulator of receptor signalling in immune cells but its role in human cancer is ill defined. Here we report that SLAP is abundantly expressed in healthy epithelial intestine but strongly downregulated in 50% of colorectal cancer. SLAP overexpression suppresses cell tumorigenicity and invasiveness while SLAP silencing enhances these transforming properties. Mechanistically, SLAP controls SRC/EPHA2/AKT signalling via destabilization of the SRC substrate and receptor tyrosine kinase EPHA2. This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2. SRC phosphorylates EPHA2 on Tyr594, thus creating a feedback loop that promotes EPHA2 destruction and thereby self-regulates its transforming potential. SLAP silencing enhances SRC oncogenicity and sensitizes colorectal tumour cells to SRC inhibitors. Collectively, these data establish a tumour-suppressive role for SLAP in colorectal cancer and a mechanism of SRC oncogenic induction through stabilization of its cognate substrates.

Date: 2014
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DOI: 10.1038/ncomms4159

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