Activation of Src and transformation by an RPTPα splice mutant found in human tumours

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Receptor protein tyrosine phosphatase α (RPTPα) is crucial for the survival of colon and breast cancer cells via Src activation.
• Aberrant RPTPα activity is implicated in cancer development.

Purpose of the Study:

• To investigate the role of mutated RPTPα in human carcinogenesis.
• To elucidate the mechanism by which RPTPα mutants activate Src kinase.

Main Methods:

• Sequencing of RPTPα cDNAs from various human tumors (colon, breast, liver).
• Expression of RPTPα245 mutant in rodent fibroblasts to study its effect on Src activation.
• RNA interference (RNAi) to block Src or endogenous RPTPα (eRPTPα) activity.
• Tumorigenicity assays in nude mice.

Main Results:

• Splice mutants of RPTPα were identified in approximately 30% of colon, breast, and liver tumors.
• A specific mutant, RPTPα245, lacking catalytic activity, was found in all three tumor types.
• RPTPα245 expression correlated with Src dephosphorylation in tumors and activated Src in fibroblasts through a novel mechanism involving binding to eRPTPα.
• This interaction decreased eRPTPα-Grb2 binding, leading to increased Src dephosphorylation by eRPTPα.
• RPTPα245-induced fibroblast transformation and tumorigenicity in mice were dependent on eRPTPα and Src activity.

Conclusions:

• Mutated RPTPα, specifically RPTPα245, contributes to human carcinogenesis by activating Src kinase.
• The novel mechanism of Src activation involves RPTPα245 binding to eRPTPα, modulating its interaction with Grb2 and enhancing Src dephosphorylation.
• Targeting RPTPα or Src may offer therapeutic strategies for RPTPα-driven cancers.