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 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.

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BibTeX RIS

BibTeX

@article{naim2026slap,
  title = {{Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis}},
  author = {Dana Naim and Zouheir Houhou and Florent Cauchois and Kevin Espie and Valérie Simon and Yvan Boublik and Francina Langa Vives and Zeinab Homayed and Conception Paul and Morgan Maillard and Michael Hahne and Julie Pannequin and Julie Nguyen and Audrey Sirvent and Serge Roche},
  journal = {eLife},
  year = {2026},
  month = aug,
  doi = {10.7554/elife.110324.2},
  url = {https://hal.science/hal-05744324v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis
AU  - Dana Naim
AU  - Zouheir Houhou
AU  - Florent Cauchois
AU  - Kevin Espie
AU  - Valérie Simon
AU  - Yvan Boublik
AU  - Francina Langa Vives
AU  - Zeinab Homayed
AU  - Conception Paul
AU  - Morgan Maillard
AU  - Michael Hahne
AU  - Julie Pannequin
AU  - Julie Nguyen
AU  - Audrey Sirvent
AU  - Serge Roche
PY  - 2026
DA  - 2026/08/05
JO  - eLife
DO  - 10.7554/elife.110324.2
UR  - https://hal.science/hal-05744324v1
AB  - 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.
SN  - 2050-084X
ER  -

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