Phosphatidylinositol 4,5-Bisphosphate and Cholesterol Regulators of the Calcium-Activated Chloride Channels TMEM16A and TMEM16B

Arreola, Jorge; López-Romero, Ana E.; Pérez‐Cornejo, Patricia; Rodríguez-Menchaca, Aldo A.

doi:10.1007/978-3-031-21547-6_10

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Cited by 3 publications

References 102 publications

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The tether function of the anoctamins

Lin,

Chung,

Muallem

2024

Cell Calcium

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The tether function of the anoctamins

Lin,

Chung,

Muallem

2024

Cell Calcium

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Insights into the function and regulation of the calcium-activated chloride channel TMEM16A

Arreola,

López-Romero,

Huerta

et al. 2024

Cell Calcium

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Missense mutations in the calcium-activated chloride channel TMEM16A promote tumor growth by activating oncogenic signaling in Human Cancer

Cruz-Rangel,

De Jesus-Perez,

Gopalkrishnan

et al. 2023

Preprint

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The calcium-activated chloride channel TMEM16A is overexpressed in several tumors. This condition is associated with a poor survival prognosis but highlights the potential of TMEM16A as a biomarker and target for anti-cancer therapies. Numerous somatic mutations of TMEM16A have been reported; however, their potential and molecular mechanism of oncogenesis are unknown. Here, we investigate the function and oncogenicity of nine-point mutations found in human cancerous tissues (R451P, R455Q, M546I, R557W, F604L, D902N, K913E, D914H, and Q917K). These mutations are located on the extracellular side and near the third Ca2+-binding site, near a PtdIns(4,5)P2 site in the human TMEM16A channel. Our findings reveal that these mutations affected gating, Ca2+sensitivity, phosphorylation of essential signaling proteins, cell proliferation, and tumor growth. Notably, R451P and D902N exhibit low Ca2+sensitivity, yet their overexpression promotes phosphorylation of EGFR and AKT, as well as in vivo tumorigenesis, without Ca2+-enhancing stimuli. Conversely, the charged-neutralizing mutation R451Q and the conservative mutation D902E restored Ca2+sensitivity and altered cell proliferation and tumor growth as wild-type did. Thus, we conclude that the oncogenic phenotype of TMEM16A missense mutations is independent of chloride flux but involves the differential activation of cell signaling components associated with cell proliferation.

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Phosphatidylinositol 4,5-Bisphosphate and Cholesterol Regulators of the Calcium-Activated Chloride Channels TMEM16A and TMEM16B

Cited by 3 publications

References 102 publications

The tether function of the anoctamins

The tether function of the anoctamins

Insights into the function and regulation of the calcium-activated chloride channel TMEM16A

Missense mutations in the calcium-activated chloride channel TMEM16A promote tumor growth by activating oncogenic signaling in Human Cancer

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