Abstract
One of the most common links between cancer and endocytosis is defective internalization of Receptor Tyrosine Kinases, for example, linked to a deficit in endocytic proteins. This scenario leads to hypersignaling and in turn to malignant transformation. Nevertheless, there are also cases in which endocytic proteins, such as the epsin adaptors, are found upregulated in invasive cancers. Indeed, we demonstrated that overexpression of the epsins enhances cancer cell migration and invasion. Furthermore, depletion of epsins (by siRNA) led to impairment of cancer cell invasion. However, the different epsin paralogs varied in their capacity to enhance migration/invasion in the following order: epsin 3 > epsin2 >> epsin1. The epsin paralogs have a highly conserved Epsin N-terminal Homology or the ENTH domain (N-terminus) and a C-terminus where the most divergent regions are housed. While our data shows that both the ENTH domain and the C-terminus are required for enhancing migration, we speculate that the differential ability of the paralogs to migrate/invade lies in their less conserved C-terminus region.
This study aims to uncover the mechanism by which epsin overexpression leads to enhanced migration/invasion and to identify the regions of the epsin C-terminus which gives the paralogs their differential ability to enhance migration/invasion. Here we describe a systematic combinatorial approach for mapping the epsin determinants involved in localizing epsin at endocytic sites and required for its effect on cancer cell migration/invasion. Our data clearly shows that Clathrin binding motifs (out of the 4 types of endocytic determinants) are the strongest localization determinants of epsin2, however are not sufficient. Infact, 2 types of endocytic determinants are required for proper epsin2 localization suggesting co-operativity and redundancy. We also found that mutation of any 2 types of endocytic determinants can also reduce the ability of epsin2 to migrate as compared to the wild-type protein. Expanding the results obtained from epsin2 to epsin3 will reveal the similarities and differences between the paralogs. Taking together our findings and the requirement of these proteins for cancer cell invasion, we envision epsin2 and epsin3 as targets for novel anti-cancer and anti-metastatic approaches.
Citation Format: Kayalvizhi Madhivanan, R. Claudio Aguilar. Role of the endocytic adaptor Epsin in cancer cell migration. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A46.
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