Description Mutant forms of a phospholipase C isoform mediate oncogenic signaling in uveal melanoma. A driver oncogene for uveal melanoma Uveal melanoma (UM) is an aggressive form of cancer that… Click to show full abstract
Description Mutant forms of a phospholipase C isoform mediate oncogenic signaling in uveal melanoma. A driver oncogene for uveal melanoma Uveal melanoma (UM) is an aggressive form of cancer that arises in the eye and lacks treatment options when it has become metastatic—the stage at which many patients with UM is diagnosed. Some UMs have mutations in the gene encoding the phospholipase PLCβ4. Phan et al. found that these mutations constitutively activated PLCβ4 and related isoforms, and proliferation was increased in melanocytes expressing these mutants. Expressing the UM-associated PLCβ4 mutant in cutaneous melanocytes induced proliferation in culture and tumorigenesis in mice. The findings reveal that PLCβ4 mediates oncogenic signaling in UM, and thus, targeting known mediators downstream of PLCβ4 (such as the kinase MEK, for which inhibitors exist) may be effective at treating this subset of UM. Activating mutations in Gαq/11 proteins are frequent in uveal melanoma, the most common eye cancer arising from the uveal tract. A small proportion of uveal melanomas have a D630Y mutation in phospholipase C β4 (PLCβ4), an effector of Gαq/11. Here, we found that the D630Y mutation in PLCβ4 results in a high level of constitutive PLCβ4 activity. Mutations at the corresponding position in other PLC isoforms also resulted in constitutive activity, revealing an unrecognized mechanism underlying PLC activation. In cultured human uveal melanoma cell lines, inhibition of PLC suppressed proliferation in Gαq/11-dependent cells. Furthermore, we found that PLCβ4(D630Y) mediated proliferation in cutaneous melanocytes and the growth of melanomas in mice. These results are consistent with PLCβ4(D630Y) driving oncogenic signaling downstream of Gαq/11.
               
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