Differential requirements for STRAD in LKB1-dependent functions in C. elegans.
The protein kinase LKB1 is a crucial regulator of cell growth/proliferation and cell polarity and is the causative gene in the cancer-predisposing disease Peutz-Jeghers syndrome (PJS). The activity of LKB1 is greatly enhanced following its association with the Ste20-like adapter protein STRAD. Unlike LKB1 however, mutations in STRAD have not been identified in PJS patients and thus, the key tumour suppressive role(s) of LKB1 might be STRAD independent. Here, we report that Caenorhabditis elegans strd-1/STRAD mutants recapitulate many phenotypes typical of par-4/LKB1 loss of function, showing defects during early embryonic and dauer development. Interestingly, although the growth/proliferation defects in severe par-4 and strd-1 mutant dauers are comparable, strd-1 mutant embryos do not share the polarity defects of par-4 embryos. We demonstrate that most of par-4-dependent regulation of germline stem cell (GSC) quiescence occurs through AMPK, whereby PAR-4 requires STRD-1 to phosphorylate and activate AMPK. Consistent with this, even though AMPK plays a major role in the regulation of cell proliferation, like strd-1 it does not affect embryonic polarity. Instead, we found that the PAR-4-mediated phosphorylation of polarity regulators such as PAR-1 and MEX-5 in the early embryo occurs in the absence of STRD-1. Thus, PAR-4 requires STRD-1 to phosphorylate AMPK to regulate cell growth/proliferation under reduced insulin signalling conditions, whereas PAR-4 can promote phosphorylation of key proteins, including PAR-1 and MEX-5, to specify early embryonic polarity independently of STRD-1. Our results therefore identify a key strd-1/STRAD-independent function of par-4/LKB1 in polarity establishment that is likely to be important for tumour suppression in humans.
Narbonne
Patrick
P
Department of Biology, McGill University, Québec, Canada.
Hyenne
Vincent
V
Li
Shaolin
S
Labbé
Jean-Claude
JC
Roy
Richard
R
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D005854:Germ Cells / Q000166:cytology; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D010580:Peutz-Jeghers Syndrome / Q000209:etiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; C410587:MEX-5 protein, C elegans; C546590:STRD-1 protein, C elegans; C097238:PAR-3 protein, C elegans; D017346:Protein Serine-Threonine Kinases; C510541:AAK-2 protein, C elegans; D055372:AMP-Activated Protein Kinases