Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis
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 (AOM/DSS) model. Slap deficiency also enhances SFK-dependent expansion of normal and tumor-derived colonic organoids. Mechanistically, we identify the receptor tyrosine kinase EphB2, an upstream activator of SFKs and CEC proliferation, as an additional SLAP-regulated target. Together, these findings reveal a non-genetic mechanism by which SFKs drive colonic transformation and establish SLAP as a tumor suppressor that constrains oncogenic SFK signaling in the colonic epithelium.
Authors
- Dana Naim (ORCID: https://orcid.org/0000-0002-4982-8381)
- Francina Langa‐Vives (ORCID: https://orcid.org/0000-0002-0801-5464)
- Julie Pannequin (ORCID: https://orcid.org/0000-0002-9956-373X)
- Serge Roche (ORCID: https://orcid.org/0000-0003-3413-3859)
- Julie Nguyen (ORCID: https://orcid.org/0000-0001-9464-2597)
- Zeinab Homayed (ORCID: https://orcid.org/0000-0003-4361-3969)
- Florent Cauchois
- Conception PAUL
- Audrey SIRVENT
- Zouheir HOUHOU
- Michael HAHNE
- Valerie SIMON
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Institute for Neurosciences of Montpellier (FR)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-05
- DOI
- https://doi.org/10.64898/2026.01.05.697659
- Primary Topic
- Axon Guidance and Neuronal Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Biogen
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Université de Montpellier
- Direction Générale de l’offre de Soins
- Région Occitanie Pyrénées-Méditerranée
- European Regional Development Fund