Interaction of HS1BP3 with cortactin modulates TKS5 localisation, cell secretion and cancer malignancy

The HCLS1-Binding Protein 3 (HS1BP3) interacts with the SH3 domain of cortactin (CTTN), a protein that contributes to a malignant phenotype in cancers. Here, we demonstrate that high expression of HS1BP3 is associated with reduced survival for gastric adenocarcinoma and triple negative breast carcinoma patients and that HS1BP3 is specifically upregulated in these cancers. We mapped the HS1BP3-cortactin interaction site to the third proline-rich region (PRR3.1) of HS1BP3 and show that this interaction is important for cancer cell proliferation, extracellular matrix degradation and secretion. HS1BP3 expression was found to correlate with expression of the invadopodia scaffold protein TKS5 and we show that the localisation of TKS5 inside multivesicular endosomes is increased in cells expressing an HS1BP3 PRR3.1 mutant. Overall, our results highlight the importance of the direct interaction between HS1BP3 and cortactin in cancer development by regulating cell proliferation, secretion and invasion, which may provide an explanation for the negative correlation between HS1BP3 levels and the survival of gastric adenocarcinoma and triple negative breast cancer patients.