Interaction of HS1BP3 with cortactin modulates TKS5 localisation and cancer malignancy

We have previously shown that HS1BP3 interacts with the SH3 domain of cortactin, a protein that contributes to a malignant phenotype in cancers. Here we demonstrate that high expression of HS1BP3 is predictive of poorer outcomes for gastric adenocarcinoma and triple negative breast carcinoma patients. We mapped the HS1BP3-SH3 interaction site to the third proline rich region (PRR3.1) of HS1BP3 and show that cells expressing an HS1BP3 PRR3.1 mutant failed to rescue the reduced proliferation and matrix degradation observed in HS1BP3 depleted cells. Moreover, the HS1BP3 PRR3.1 mutant was found to modulate the mRNA levels of the invadopodia scaffold protein TKS5 in gastric cancer cells and contribute to buildup of TKS5 inside multivesicular endosomes in both gastric and TNBC cells. Overall, our results highlight the importance of the direct interaction between the HS1BP3 PRR3.1 and the cortactin SH3 domain in cancer development by regulating endosomal trafficking and cytoskeleton arrangements.