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

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• The adaptor SLAP (Src homology 2 domain-containing T-cell-activating phosphoprotein) is a known negative regulator of receptor signaling in immune cells.
• Its specific role in human cancer, particularly colorectal cancer, remains largely undefined.

Purpose of the Study:

• To investigate the role of SLAP in colorectal cancer development and progression.
• To elucidate the molecular mechanisms by which SLAP influences cancer cell tumorigenicity and invasiveness.

Main Methods:

• Analysis of SLAP expression in healthy intestine versus colorectal cancer tissues.
• Assessment of SLAP's impact on cell tumorigenicity and invasiveness through overexpression and silencing studies.
• Investigation of SLAP's interaction with SRC, EPHA2, AKT, CBL, and UBE4A signaling pathways.
• Examination of EPHA2 phosphorylation and destabilization mediated by SLAP.

Main Results:

• SLAP is downregulated in approximately 50% of colorectal cancers.
• SLAP overexpression suppresses, while SLAP silencing enhances, colorectal cancer cell tumorigenicity and invasiveness.
• SLAP controls SRC/EPHA2/AKT signaling by destabilizing the SRC substrate EPHA2, requiring interaction with UBE4A and pTyr594-EPHA2.
• SLAP silencing enhances SRC oncogenicity and sensitizes colorectal tumor cells to SRC inhibitors.

Conclusions:

• SLAP acts as a tumor suppressor in colorectal cancer.
• SLAP's tumor-suppressive function is mediated by the destabilization of EPHA2, a key event in regulating SRC oncogenicity.
• Understanding SLAP's role provides potential therapeutic targets for colorectal cancer treatment.