Auto-inhibitory intramolecular S5/S6 interaction in the TRPV6 channel regulates breast cancer cell migration and invasion.
Auto-inhibitory intramolecular S5/S6 interaction in the TRPV6 channel regulates breast cancer cell migration and invasion.
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TRPV6通道中的自抑制分子内S5/S6相互作用调节乳腺癌细胞迁移和侵袭
DOI：
10.1038/s42003-021-02521-3
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发表时间：
2021-08-19
影响因子：
5.9
通讯作者：
Chen XZ
中科院分区：
文献类型：
--
作者：
Cai R;Wang L;Liu X;Michalak M;Tang J;Peng JB;Chen XZ
TRPV 6是一种钙离子选择性通道，在胎盘、肠、肾和骨髓中大量表达。TRPV 6对Ca稳态至关重要，其缺陷表达或功能与短暂性新生儿甲状旁腺功能亢进、Lowe综合征/Dent病、肾结石、骨质疏松症和癌症有关。TRPV 6的功能和调节的分子机制仍然没有得到很好的理解，这一事实阻碍了人们对TRPV 6如何促进乳腺癌发展的理解。通过电生理学和钙成像在非洲爪蟾卵母细胞和癌细胞，分子生物学和数值模拟，在这里，我们揭示了一个分子内的S5/S6螺旋相互作用的TRPV 6的功能是自抑制和介导的R532：D 620键。S5内预测的致病性突变R532 Q破坏了S5/S6相互作用，导致该通道的功能获得，其通过加强TRPV 6/PI 3 K相互作用、激活PI 3 K/Akt/GSK-3β级联以及上调上皮-间充质转化和抗凋亡来促进乳腺癌细胞进展。Cai等人发现了钙选择性通道TRPV 6中S5和S6螺旋之间的自抑制相互作用。分子动力学模拟预测S5中致病性突变R532 Q导致通道功能获得，这在乳腺癌迁移、侵袭和凋亡测定中得到证实。
TRPV6, a Ca-selective channel, is abundantly expressed in the placenta, intestine, kidney and bone marrow. 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 Xenopus 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-3β cascade, and up-regulation of epithelial-mesenchymal transition and anti-apoptosis. Cai et al discover an auto-inhibitory interaction between the S5 and S6 helices in the calcium-selective channel TRPV6. Molecular dynamics simulations predict that pathogenic mutation R532Q in S5 results in channel gain-of-function, which is confirmed in breast cancer migration, invasion and apoptosis assays.
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DOI：
10.1085/jgp.118.2.157
发表时间：
2001-08
期刊：
The Journal of general physiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.2
作者：
Bolanz, Katrin A.;Kovacs, Gergely Gy.;Hediger, Matthias A.
通讯作者：
Hediger, Matthias A.
影响因子：
8
作者：
Lehen'kyi, V.;Flourakis, M.;Prevarskaya, N.
通讯作者：
Prevarskaya, N.
影响因子：
16.6
作者：
Hughes TET;Pumroy RA;Yazici AT;Kasimova MA;Fluck EC;Huynh KW;Samanta A;Molugu SK;Zhou ZH;Carnevale V;Rohacs T;Moiseenkova-Bell VY
通讯作者：
Moiseenkova-Bell VY
影响因子：
--
作者：
Dhennin-Duthille, Isabelle;Gautier, Mathieu;Ouadid-Ahidouch, Halima
通讯作者：
Ouadid-Ahidouch, Halima