The cadherin-based adherens junction (AJ) is a critical cell-cell adhesion apparatus, misregulation of which leads to development failures and cancers. The formation of AJs is known to be dependent on the assembly of a local actin network, but the regulation of this remains unclear. Our preliminary data suggest that talin, a protein known for its role in the regulation of the actin network associated with integrin-based cell-matrix adhesion, is also involved in the AJ through a novel talin proteolytic fragment containing the vinculin- and actin- binding domains and a dimerizing region (referred as the VAD fragment). This fragment also undergoes posttranslational arginylation in vivo. We hypothesize that the proteolysis alters the domain architecture of talin, allowing the resulting VAD fragment to localize to the cadherin- based AJ. There the fragment enhances local actin assembly with its functional domains and stabilizes the AJ. Furthermore, arginylation changes the affinities of the VAD fragment to its binding partners and enhances its physiological function in AJs. In this proposed study we will test this hypothesis in these three specific aims: (1) How is the talin VAD fragment recruited to the cadherin-mediated AJ, and how does it enhance actin assembly? (2) Is the formation of cadherin-based AJs dependent on the VAD fragment? (3) How does arginylation enhance the function of the VAD fragment? Through this study, we will elucidate a novel regulatory mechanism for cadherin-based cell-cell adhesions mediated by the novel processing of talin, which was traditionally considered only associated with integrin-based adhesions. Also this project will provide new insight into how the conserved but poorly understood posttranslational arginylation modification affects protein function in cells.
This project will reveal new insights into the regulation of the formation of cell-cell adhesions. As such it is directly relevant to embryo development, tissue formation and regeneration, and pathogenesis and progress of cancers.
|Birnbaum, Michael D; Zhao, Ning; Moorthy, Balaji T et al. (2018) Reduced Arginyltransferase 1 is a driver and a potential prognostic indicator of prostate cancer metastasis. Oncogene :|
|Kumar, Akhilesh; Birnbaum, Michael D; Patel, Devang M et al. (2016) Posttranslational arginylation enzyme Ate1 affects DNA mutagenesis by regulating stress response. Cell Death Dis 7:e2378|
|LeBlanc, Michelle E; Wang, Weiwen; Chen, Xiuping et al. (2016) The regulatory role of hepatoma-derived growth factor as an angiogenic factor in the eye. Mol Vis 22:374-86|
|Zhang, Fangliang; Patel, Devang M; Colavita, Kristen et al. (2015) Arginylation regulates purine nucleotide biosynthesis by enhancing the activity of phosphoribosyl pyrophosphate synthase. Nat Commun 6:7517|