Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis.

Authors

Dana Naim, Zouheir Houhou, Florent Cauchois, Kevin Espie, Valerie Simon, Yvan Boublik, Francina Langa Vives, Zeinab Homayed, Conception Paul, Morgan Maillard, Michael Hahne, Julie Pannequin, Julie Nguyen, Audrey Sirvent, Serge Roche

Published in

eLife. Volume 15. Sep 08, 2026. Epub Sep 08, 2026.

Abstract

Src-family kinases (SFKs) regulate proliferation in colonic epithelial cells (CECs), but the mechanisms that restrain their activity remain poorly defined. We identify Src-like adaptor protein (SLAP), a negative regulator of receptor tyrosine kinase signaling, as a key suppressor of SFK activity in the colon. Constitutive and inducible epithelial-specific Slap deletion using a villin-CreERT2 model increases CEC proliferation and accelerates tumorigenesis in the azoxymethane/dextran sodium sulfate model. Slap deficiency also enhances SFK-dependent expansion of normal and tumor-derived colonic organoids. Mechanistically, we identify the receptor tyrosine kinase EPHB2 as a critical upstream activator of SFKs and a direct target of SLAP-mediated regulation. Loss of Slap increased EphB2 protein abundance and tyrosine phosphorylation, and enhanced its association with active SRC. Pharmacological inhibition of EPHB2 suppressed SRC activation and reversed the hyperproliferative phenotype induced by Slap deficiency. Together, these findings uncover a non-genetic mechanism driving SFK activation during colonic transformation and establish SLAP as a tumor suppressor that constrains oncogenic EPHB2-SFK signaling in the colonic epithelium.

PMID:
42709470
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

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