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EPS8 phosphorylation by Src modulates its oncogenic functions.

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|July 10, 2020
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Summary
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Investigating Epidermal Plasmacytoma Expressed Sequence 8 (EPS8) phosphorylation in head and neck squamous cell carcinoma (HNSCC) reveals Y602 phosphorylation is key for cell cycle signaling. This finding may explain why dasatinib treatment is less effective in some cancers.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Epidermal Plasmacytoma Expressed Sequence 8 (EPS8) is a scaffolding protein implicated in cancer progression.
  • Increased EPS8 expression correlates with enhanced tumor growth, migration, and proliferation.
  • The functional significance of Src-mediated tyrosine phosphorylation of EPS8 remains largely unknown.

Purpose of the Study:

  • To investigate the pro-oncogenic role of EPS8 tyrosine phosphorylation at Src target sites in head and neck squamous cell carcinoma (HNSCC).
  • To elucidate the impact of specific EPS8 phosphorylation sites on cellular functions and tumorigenicity.

Main Methods:

  • Generated EPS8 mutants with phenylalanine substitutions at Src target tyrosine residues (Y485F, Y525F, Y602F, Y774F, and FFFF).
  • Expressed these mutants in cells and treated with dasatinib to inhibit Src activity.
  • Assessed downstream targets, proliferation, migration, and tumorigenicity.

Main Results:

  • EPS8 phosphorylation at Y602 and the combined FFFF mutant significantly reduced mitogenesis and motility.
  • Conversely, Y602F and FFFF EPS8 mutants unexpectedly promoted tumorigenicity.
  • Dasatinib treatment decreased EPS8 downstream targets, but Y602 phosphorylation's role in cell cycle signaling may affect drug efficacy.

Conclusions:

  • Phosphorylation of EPS8 at tyrosine 602 (Y602) is critical for signaling pathways regulating the cell cycle.
  • Understanding EPS8 phosphorylation at Y602 offers insights into the reduced efficacy of dasatinib in certain HNSCC cases.