The N-terminal domain of the adaptor protein p140Cap interacts with Tiam1 and controls Tiam1/Rac1 axis.

ABSTRACT

The p140Cap adaptor protein, encoded by the SRCIN1 gene, negatively controls tumor progression, as demonstrated in the subgroup of HER2-amplified breast cancers and in neuroblastoma patients, where high p140Cap expression predicts a decreased probability of developing metastasis, with a significantly prolonged survival. In NeuT mice, a preclinical model or Her2-positive breast cancer, we previously reported that p140Cap counteracts Her2-dependent breast cancer progression, associating with the specific Rac1 Guanine Nucleotide Exchange Factor, Tiam1, and limiting the activation of both Tiam1 and Rac1. Here, we show that in TUBO breast cancer cells derived from the NeuT tumors, p140Cap expression causes Tiam1 redistribution along the apicobasal junctional axis. Furthermore, p140Cap and Tiam1 interact with E-cadherin, a member of the adherence junction, with a concomitant increase of E-cadherin at the cell membrane. We characterized biochemically the interaction between p140Cap and Tiam1, showing that the amino terminal region of p140Cap (1-287 amino acids) is sufficient to associate with full length Tiam1, and with the truncated catalytic domain of Tiam1, with a concomitant decrease of the Tiam1 activity. Moreover, in a large cohort of Her2 positive breast cancer, high levels of SRCIN1 expression positively correlates with increased survival in patients with high TIAM1 expression. Overall, our findings sustain a protective role of p140Cap in Her2 positive breast cancer, where p140Cap can associate with Tiam1 and negatively regulate the Tiam1/Rac1 axis.