Inositol (1,4,5)-trisphosphate 5-phosphatase promotes survival of uveal melanoma by regulating oncogenic G protein–driven calcium oscillations

Mutant constitutively active (CA) G protein α-subunits encoded by GNAQ or GNA11 (CA-GNAQ/11) drive uveal melanoma (UM), occur in uncommon subtypes of other cancers, and cause Sturge–Weber syndrome and other capillary malformations. CA-GNAQ/11 activates phospholipase Cβ, which cleaves phosphatidylinositol (4,5)-bisphosphate at high rate to produce diacylglycerol that drives oncogenesis and inositol (1,4,5)-trisphosphate (IP3) that releases Ca²⁺ from intracellular stores and triggers store-operated Ca²⁺ entry. For poorly understood reasons, high IP3 flux in UM cells does not elicit Ca²⁺ overload and death. To address this question, we studied INPP5A, a farnesylated, membrane-bound inositol polyphosphate 5-phosphatase that degrades IP3. We showed that INPP5A is upregulated in and required by CA-GNAQ/11-driven UM cell lines and is genetically preserved in UM tumors. We found that INPP5A is reversibly palmitoylated, which together with farnesylation targets the enzyme to subcellular compartments and regulates Ca²⁺ mobilization. Although CA-GNAQ/11 is constitutively active, we discovered that it drives low-frequency Ca²⁺ oscillations in UM cells. We found that acute inhibition of INPP5A in UM cells augments Ca²⁺ oscillation rate, a diagnostic effect of elevating IP3 levels. These results indicated that INPP5A safeguards CA-GNAQ/11-driven UM tumors against Ca²⁺ overload and death by regulating IP3-evoked Ca²⁺ oscillations. As universal frequency–encoded signals, Ca²⁺ oscillations likely regulate vital functions in UM cells. Our findings suggest strategies for targeting INPP5A in diseases or disorders driven by CA-GNAQ/11.