SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2.
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.
CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2, 34000 Montpellier, France.
Cécile
C
Naudin
CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2, 34000 Montpellier, France.
Audrey
A
Sirvent
1] CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2, 34000 Montpellier, France [2].
Cédric
C
Leroy
CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2, 34000 Montpellier, France.
Romain
R
Larive
CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2, 34000 Montpellier, France.
Valérie
V
Simon
CNRS UMR5203, INSERM U661, Institut de Génomique Fonctionnelle, University of Montpellier 1 and 2, 34000 Montpellier, France.
Julie
J
Pannequin
Department of Gastroenterology, CHU Carémeau, 30000 Nîmes, France.
Jean-François
JF
Bourgaux
INSERM U749, Institut Gustave Roussy, 94800 Villejuif, France.
Josiane
J
Pierre
INSERM U896, Institut de Recherche en Cancérologie de Montpellier, University of Montpellier 1 and 2, 34000 Montpellier, France.
Bruno
B
Robert
1] CNRS UMR5203, INSERM U661, Institut de Génomique Fonctionnelle, University of Montpellier 1 and 2, 34000 Montpellier, France [2] Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Frédéric
F
Hollande
CNRS UMR5237, Centre de Recherche en Biochimie Macromoléculaire, University of Montpellier 1 and 2, 34000 Montpellier, France.
Serge
S
Roche
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism* / Q000502:physiology; D036104:Receptor, EphA2 / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C490635:SLA protein, human; C486451:UBE4A protein, human; D044767:Ubiquitin-Protein Ligases; D036104:Receptor, EphA2; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt