DAF-18/PTEN signals through AAK-1/AMPK to inhibit MPK-1/MAPK in feedback control of germline stem cell proliferation

Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS) and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems.Stem cell proliferation rates can further be locally refined to meet the resident tissue's need for differentiated progeny.We have recently shown that the accumulation of mature oocytes in the C. elegans germ line, through DAF-18/PTEN, inhibits adult germline stem cell (GSC) proliferation, despite high systemic IIS activation.We show here that this feedback occurs through a novel cryptic signalling pathway that requires PAR-4/LKB1, AAK-1/AMPK and PAR-5/14-3-3 to inhibit the activity of MPK-1/MAPK, antagonize IIS, and inhibit both GSC proliferation and the production of additional oocytes.Interestingly, our results imply that DAF-18/PTEN, through PAR-4/LKB1, can activate AAK-1/AMPK in the absence of apparent energy stress.As all components are conserved, similar signalling cascades may regulate stem cell activities in other organisms and be widely implicated in cancer. Author summaryAdult stem cell proliferation rates respond to the needs for their differentiated progeny.For example, the lung stem cells of a smoker will divide more frequently than those of a non-smoker to constantly replenish smoke-damaged tissues.Molecularly, stem cell proliferation rates vary according to growth factor levels, some of which, such as insulin, are regulated systemically.What remains unclear is whether and how a more or less rapid turnover of differentiated cells interferes with growth factor signalling to ultimately set the stem cells' proliferative rate.We show here that this is accomplished though a novel cryptic signalling pathway that locally antagonizes the effects of insulin through inactivating a more locally-acting growth factor pathway (ERK/MAPK signalling).Interestingly, a ubiquitous protein kinase (AMPK) that has primarily been implicated in energy stress