A novel regulator of ER Ca²⁺ drives Hippo-mediated tumorigenesis.

Calcium ion (Ca²⁺) is a versatile second messenger that regulates various cellular and physiological functions. However, the in vivo molecular mechanisms by which Ca²⁺ alterations contribute to tumor growth remain poorly explored. Here we show that Emei is a novel ER Ca²⁺ regulator that synergizes with Ras^V12 to induce tumor growth via JNK-mediated Hippo signaling. Emei disruption reduces ER Ca²⁺ level and subsequently leads to JNK activation and Hippo inactivation. Importantly, genetically increasing cytosolic Ca²⁺ concentration cooperates with Ras^V12 to drive tumor growth via inactivating the Hippo pathway. Finally, we identify POSH as a crucial link that bridges cytosolic Ca²⁺ alteration with JNK activation and Hippo-mediated tumor growth. Together, our findings provide a novel mechanism of tumor growth that acts through intracellular Ca²⁺ levels to modulate JNK-mediated Hippo signaling.

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