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

Abstract

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.

Low expression of PTEN is essential for maintenance of a malignant state in human gastric adenocarcinoma via upregulation of p‑AURKA mediated by activation of AURKA

“…According to the present study, PTEN inhibited tumorigenesis by interacting with genes or modulating multiple signal transduction pathways (34)(35)(36). To further examine the effects of the reduced expression of PTEN on other intracellular signaling pathways in gastric cancer cells, the expression of key molecules in the signaling pathways of MGc803 and SGc7901 cells were investigated.…”

AMPK regulates germline stem cell quiescence and integrity through an endogenous small RNA pathway

“…Although, morphologically many of the proximal germ cells appear to undergo cellularization and oogenesis, at the nuclear level they fail to complete diakinesis to form 6 condensed nuclear bodies; a hallmark of a mature oocyte and thus fails to produce a functional matured oocyte (30). AMPK has been shown to regulate the MAPK pathway to block the germ cell divisions under nutritional stress (31). Therefore, perhaps during the energy stress associated with the dauer stage, AMPK could regulate key components of the MAPK pathway to modulate meiotic cell cycle progression thereby delaying the production of mature oocytes, and ensuring that reproductive development is coordinated with transit through the dauer stage.…”

Non-autonomous regulation of germline stem cell proliferation by somatic MPK-1/MAPK activity inC. elegans

“…Proliferation is reduced in mpk-1(ø) mutants 18,20,21 , but also reduced upon removal of LIP-1, an MPK-1 inhibitory phosphatase that is expressed in germline stem cells (GSCs) 22 . Regardless, germline proliferation continues into adulthood in mpk-1(ø) mutants 21 . Therefore, as in other species and other stem cell types, nematode ERK/MAPK is essential for differentiation but not for stem cell proliferation.…”

“…GSCs, together with their proliferating progeny, span a region in the distal gonad termed the progenitor zone (PZ) ( Figure 1A, right). The rate of GSC proliferation is inferred from the mitotic index measured across the PZ 20,21,27,28 . In adult hermaphrodites, GSC proliferation rates influence distal-to-proximal germ cell flow, and are thus linked to the pace of oocyte production 29 .…”

“…1B), a regulation conserved in C. elegans, Drosophila and likely mammals [30][31][32][33][34][35][36] . Most relevant here, downstream IIS effectors act autonomously within the germline 21,34 . In parallel, but through an unknown mechanism, MPK-1 signaling combines with IIS to promote the high proliferation typical of young adult hermaphrodites (Fig.…”