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

Patrick Narbonne,Jean-Claude Labbé,Paul S Maddox,Giovanni Bosco

doi:10.1371/journal.pgen.1006738

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.

Highlights

Stem cells can divide symmetrically to generate more copies of themselves or asymmetrically to produce one stem cell and a daughter cell destined for differentiation
Stem cell proliferation rates vary according to growth factor levels, some of which, such as insulin, are regulated systemically
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)

Summary

Introduction

Stem cells can divide symmetrically to generate more copies of themselves or asymmetrically to produce one stem cell and a daughter cell destined for differentiation. Dauer entry is naturally promoted by food deprivation, which causes energy stress and leads to a down-regulation of IIS and activation the AMP-activated protein kinase AAK (Ce AMPK) [14], a master intracellular energy-stress sensor [15]. In this context, the proper establishment of GSC quiescence downstream of insulin receptor inactivation requires DAF-18 (Ce PTEN), PAR-4 (Ce LKB1; an AMPK-activating kinase [15]), as well as germline AAK activity [2,14]

Methods

Results

Discussion

Conclusion