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

Cécile Naudin (1) , Audrey Sirvent (1) , Cédric Leroy (1) , Romain Larive (1, 2) , Valérie Simon (1) , Julie Pannequin (3) , Jean-François Bourgaux (4) , Josiane Pierre (5, 6) , Bruno Robert (7) , Frédéric Hollande (3) , Serge Roche (1)

1 CRBM - Centre de recherche en Biologie Cellulaire
2 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
3 IGF - Institut de Génomique Fonctionnelle
4 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
5 BBOA - Biomécanique et biomatériaux ostéo-articulaires
6 U749 - Recepteurs et Signalisation des Interleukines
7 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier

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.

Mots clés: Colorectal Neoplasms-pathology-physiopathology; Signal Transducing-physiology; Adaptor Proteins; Humans; Signal Transduction; Tumor Suppressor; Genes; Tumor; Cell Line; Proto-Oncogene Proteins c-akt-metabolism; Proto-Oncogene Proteins pp60(c-src)-metabolism-physiology; Receptor; EphA2-metabolism; Ubiquitin-Protein Ligases-metabolism

Domaines: Sciences du Vivant [q-bio]

Cécile Naudin, Audrey Sirvent, Cédric Leroy, Romain Larive, Valérie Simon, et al.. SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2. Nature Communications, 2014, 5, pp.3159. ⟨10.1038/ncomms4159⟩. ⟨hal-01944933⟩