Auto-inhibitory intramolecular S5/S6 interaction in the TRPV6 channel regulates breast cancer cell migration and invasion

Abstract

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.

Bidirectional Allosteric Coupling between PIP2 Binding and the Pore of the Oncochannel TRPV6

“…Later, Cai et al (2021) proposed R492 to interact with D580, imposing autoinhibitory effects on the channel by stabilizing a narrow pore conformation. Hindrance due to R492Q substitution was reported to render D580 and the nearby gate region more flexible so that the pore becomes wider [ 87 ]. While the role of PIP 2 was neglected in this study, it is tempting to combine these findings with R492 as putative PIP 2 binding partner, as observed in the modeled structure [ 56 ].…”

The TRPV6 Calcium Channel and Its Relationship with Cancer

“…Conversely, TRPV6 inhibition reduces cell migration [ 52 ]. Cai et al found that the TRPV6 pathogenic mutation R532Q enhances the TRPV6/PI3K interaction, thereby activating the PI3K/Akt/GSK-3β cascade to further promote breast cancer migration [ 75 ]. TRPV6 has a strong effect on the proliferation of breast cancer cells, which are regulated by estrogen, progesterone, tamoxifen, and 1, 25-vitamin D3.…”

Transient receptor potential channels’ genes forecast cervical cancer outcomes and illuminate its impact on tumor cells

“…TRP channel-related proteins expressed in various cancer cell types such as breast, prostate, lung, colon and pancreatic malignancies, have recently attracted more research attention. Specifically, TRPV6 has been shown to promote the invasion and migration of breast cancer cells ( Cai et al, 2021 ). TRPV6 is linked to cancer cell death and proliferation in prostate cancer ( Lehen kyi et al, 2007 ).…”