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

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.