Caenorhabditis elegans DAF-18/PTEN non-autonomously prevents tumors by enhancing calcium sensitivity

Insulin/IGF-1 signaling (IIS) centrally promotes stem/progenitor proliferation during development to translate nutrition into tissue expansion. In adults however, despite ongoing feeding and systemic IIS stimulation, most tissues stop growing. How adult tissues balance out IIS-induced growth is incompletely understood. Here, we report a direct molecular link between IIS and calcium responses that permits a global reduction of germ tissue turnover rates in spermless C. elegans hermaphrodites. We show that these spermless hermaphrodites require the key negative IIS regulator DAF-18/PTEN to prevent AKT-1,2/AKT from phospho-inhibiting the highly conserved small GTPase RHO-1/RHOA in their spermathecal necks to improve their calcium sensitivity. Their increased contractility restricts ovulation and triggers oocyte accumulation along with a concomitant downregulation of GSC proliferation, stabilizing their germline in a hyperplastic state. Similar IIS-calcium cross talks may explain how IIS promotes anabolism in adult tissues without causing their expansion, and why reduced PTEN activity provokes benign differentiated hamartoma-like tumors.