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TRPV6 is vital to Ca homeostasis and its defective expression or function is linked to transient neonatal hyperparathyroidism, Lowe syndrome\/Dent disease, renal stone, osteoporosis and cancers. The fact that the molecular mechanism underlying the function and regulation of TRPV6 is still not well understood hampers, in particular, the understanding of how TRPV6 contributes to breast cancer development. By electrophysiology and Ca imaging in <jats:italic>Xenopus<\/jats:italic> oocytes and cancer cells, molecular biology and numerical simulation, here we reveal an intramolecular S5\/S6 helix interaction in TRPV6 that is functionally autoinhibitory and is mediated by the R532:D620 bonding. Predicted pathogenic mutation R532Q within S5 disrupts the S5\/S6 interaction leading to gain-of-function of the channel, which promotes breast cancer cell progression through strengthening of the TRPV6\/PI3K interaction, activation of a PI3K\/Akt\/GSK-3\u03b2 cascade, and up-regulation of epithelial-mesenchymal transition and anti-apoptosis.<\/jats:p>","DOI":"10.1038\/s42003-021-02521-3","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T10:08:51Z","timestamp":1629367731000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Auto-inhibitory intramolecular S5\/S6 interaction in the TRPV6 channel regulates breast cancer cell migration and invasion"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-0759","authenticated-orcid":false,"given":"Ruiqi","family":"Cai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4467-6638","authenticated-orcid":false,"given":"Xiong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9343-9084","authenticated-orcid":false,"given":"Marek","family":"Michalak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingfeng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-Bin","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4464-0598","authenticated-orcid":false,"given":"Xing-Zhen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"2521_CR1","doi-asserted-by":"publisher","first-page":"a003962","DOI":"10.1101\/cshperspect.a003962","volume":"2","author":"M Gees","year":"2010","unstructured":"Gees, M., Colsoul, B. & Nilius, B. 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