Maria Pilar Camacho Leal

The assembly of molecular hubs upon integrin and growth factor stimulation represents a preferential way to transduce signals throughout the cell. Among the intracellular kinases that are responsive to integrin and growth factor activation, Src Family Kinases (SFKs) are crucial regulators of cell migration and invasion. Increasing evidence highlight the importance of adaptor proteins in these processes, based on their ability to create signalling platforms that control downstream signals. Among these adaptors we will discuss the molecular features of p130Cas and p140Cap proteins in terms of regulation of cell migration and invasion in normal and transformed cells.

// Brigitte Bisaro 1 , Marianna Sciortino 1 , Shana Colombo 1 , Maria Pilar Camacho Leal 1 , Andrea Costamagna 1 , Isabella Castellano 2 , Filippo Montemurro 3 , Valentina Rossi 3 , Giorgio Valabrega 4, 2 , Emilia Turco 1 , Paola Defilippi 1 , Sara Cabodi 1 1 Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy 2 Department of Medical Sciences, University of Torino, Torino, Italy 3 Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia (FPO)-Candiolo Cancer Center (IRCCs), Torino, Italy 4 Department of Oncology, University of Torino, Torino, Italy Correspondence to: Sara Cabodi, e-mail: sara.cabodi@unito.it Keywords: p130Cas, ErbB2, autophagy, breast cancer resistance Received: June 16, 2015      Accepted: November 25, 2015      Published: December 21, 2015 ABSTRACT Overexpression of the ErbB2/HER2 receptor tyrosine kinase occurs in up to 20% of human breast cancers and correlates with aggressive disease. Several efficacious targeted therapies, including antibodies and kinase inhibitors, have been developed but the occurring of resistance to these agents is often observed. New therapeutic agents targeting the endocytic recycling and intracellular trafficking of membrane in tumor cells overexpressing ErbB2 are actually in clinical development. Nevertheless the mechanisms underlying ErbB2 downregulation are still obscure. We have previously demonstrated that the overexpression of the p130Cas adaptor protein in ErbB2 positive breast cancer, promotes tumor aggressiveness and progression. Here we demonstrate that lowering p130Cas expression in breast cancer cells is sufficient to induce ErbB2 degradation by autophagy. Conversely, p130Cas overexpression protects ErbB2 from degradation by autophagy. Furthermore, this autophagy-dependent preferential degradation of ErbB2 in absence of p130Cas is due to an increased ErbB2 ubiquitination. Indeed, the overexpression of p130Cas impairs ErbB2 ubiquitination by inhibiting the binding of Cbl and CHIP E3 ligases to ErbB2. Finally, our results indicate that p130Cas-dependent ErbB2 protection from degradation by autophagy may alter the sensitivity to the humanized monoclonal antibody trastuzumab. Consistently, in human ErbB2 positive breast cancers that develop resistance to trastuzumab, p130Cas expression is significantly increased suggesting that elevated levels of p130Cas can be involved in trastuzumab resistance.