The loss of the TSC2 gene, either inherited or sporadic, can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare lung disease characterized by cystic growths caused by tumor nodules. These nodules result from the spread of cells (LAM cells) that resemble neural crest and smooth muscle cells. The growth of these cells is driven by overactivity of mTORC1, a protein kinase that is normally suppressed by the TSC1-TSC2 complex. While the drug rapamycin inhibits mTORC1 and slows LAM progression, it does not cure the disease, suggesting the need to identify other drug targets. Previous research pointed to the urotensin-II receptor (UT) signaling pathway as a potential factor, but its role in TSC2-deficient cells was unclear. This study shows that UT signaling is hyperactive in TSC2-deficient cells, promoting their cancerous behavior through a mechanism that does not depend on mTORC1. The study finds that UT signaling activates Gαq, a protein that can activate cancer-like spread and survival of cells. This activation occurs independently of mTORC1 and is associated with a higher presence of Gαq-related proteins in cellular structures called endosomes. These findings from the Kristof lab highlight the potential for targeting mTORC1-independent pathways to treat or prevent LAM.

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