Abstract LB-018: Cleavage of SNX2 protein by initiator caspases promotes hepatocyte growth factor (MET) receptor tyrosine kinase signaling

Cell death induced by apoptosis involves the stepwise activation of initiator and executioner caspases. Unfolding of this cellular process concurs with caspase-mediated proteolysis of hundreds of proteins with the ultimate result of stopping crucial cell survival, including the intracellular endocytic receptor trafficking. During cancer progression, tumor cells often become resistance to normal death-inducing signals. Typically, this resistance involves a cellular block of the apoptotic cascade downstream of the initiator caspases. Thus, apoptosis-resistant cancer cells are endowed with the unique capacity of sustaining elevated activation of initiator caspases. Apoptosis resistance being critical for metastatic progression, it opens the question of whether the cleavage products of initiator caspases contribute to the metastatic properties of apoptosis-resistant cells. In a recent study, we identified the SNX1 and SNX2 proteins, which are members of the sorting nexin (SNX) family of proteins critical in the control of endosomal sorting, as initiator caspase substrates. In addition, we demonstrated that the cleavage of SNX2 abolished its endosomal sorting ability, as illustrated by loss of its association with the endosome-to-trans-Golgi network transport protein Vps35 and a delocalization its binding partner Vps26 from endosomes. Importantly, depletion of SNX2 in cells was shown to enhance hepatocyte growth factor-induced phosphorylation of the MET receptor tyrosine kinase (RTK) and that of Erk1/2 proteins. Furthermore, we identified reduced SNX2 mRNA and protein levels in colorectal carcinoma specimens when compared to adjacent normal tissues, and that low SNX2 mRNA expression in primary colorectal tumors correlated with poor survival of patients. Deregulation of RTK signaling, such as that of the epidermal and hepatocyte growth factor receptors, is known to contribute to metastatic progression. Signaling and biological activity of these cell surface receptors are tightly controlled by their internalization upon activation and trafficking into endosomes, where they are either recycled back to the plasma membrane or degraded in lysosomes. Thus, our novel discoveries suggest that the activation of initiator caspases in apoptosis-resistant cancer cells fosters cancer progression by selective cleavage of proteins involved in RTK endocytic trafficking. Note: This abstract was not presented at the meeting. Citation Format: Catherine M. Duclos, Audrey Champagne, Julie C. Carrier, Caroline Saucier, Christine L. Lavoie, Jean-Bernard Denault. Cleavage of SNX2 protein by initiator caspases promotes hepatocyte growth factor (MET) receptor tyrosine kinase signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-018. doi:10.1158/1538-7445.AM2017-LB-018