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Binding partner regulation of Myosin VI: Loss of tumour-suppressor Dab2 leads to enhanced activity of nuclear myosin

By Natalia Fili, Yukti Hari-Gupta, Bjork Aston, Ália dos Santos, Rosemarie E. Gough, Bana Alamad, Lin Wang, Marisa Martin-Fernandez, Christopher P. Toseland

Posted 16 May 2019
bioRxiv DOI: 10.1101/639963

Myosin VI is involved in a variety of cellular processes ranging from endocytosis to transcription. This multi-functional potential is achieved through alternative isoform splicing and through the interaction with a diverse network of binding partners. However, the interplay between the two modes of regulation remains unexplored. To this end, we have compared two different binding partners, Dab2 and CALCOCO2/NDP52, and their interaction with two myosin VI splice isoforms. We found that both isoforms adopt an auto-inhibited state and are subsequently activated by binding partner association. However, differential regulation is achieved through a high and a low affinity binding motifs within myosin VI, with one isoform having the high affinity site blocked. This allows competition between partners and links isoform splicing with binding partner selectivity. Dab2 competition hinders the activity of nuclear myosin VI by preventing DNA binding and transcription. Moreover, re-introduction of Dab2 in the Dab2-deficient MCF-7 cells leads to a decrease in myosin VI-dependent estrogen receptor gene expression. We propose that the frequent loss of Dab2 during the onset of cancer enables a higher level of nuclear myosin VI activity, thereby driving the activity of the estrogen receptor to promote tumourgenesis.

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