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PMID:20110331

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Citation

Narbonne, P, Hyenne, V, Li, S, Labbé, JC and Roy, R (2010) Differential requirements for STRAD in LKB1-dependent functions in C. elegans. Development 137:661-70

Abstract

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.

Links

PubMed Online version:10.1242/dev.042044

Keywords

AMP-Activated Protein Kinases/metabolism; Animals; Animals, Genetically Modified; Body Patterning; Caenorhabditis elegans/embryology; Caenorhabditis elegans/genetics; Caenorhabditis elegans/growth & development; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Embryonic Stem Cells/cytology; Gene Expression Regulation, Developmental; Genes, Helminth; Germ Cells/cytology; Humans; Models, Biological; Mutation; Peutz-Jeghers Syndrome/etiology; Phosphorylation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:STRD1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00003919

F

Seeded From UniProt

complete

CAEEL:STRD1

involved_in

GO:0010800: positive regulation of peptidyl-threonine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00093443

P

Seeded From UniProt

complete

CAEEL:STRD1

enables

GO:0043539: protein serine/threonine kinase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00093443

F

Seeded From UniProt

complete

CAEEL:STRD1

located_in

GO:0005938: cell cortex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:PAR4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00013132

F

Seeded From UniProt

complete

CAEEL:PAR4

involved_in

GO:0018107: peptidyl-threonine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00088027

P

Seeded From UniProt

complete

CAEEL:PAR4

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00088027

F

  • has_input:(WB:WBGene00003916)

Seeded From UniProt

complete

CAEEL:PAR4

located_in

GO:0005938: cell cortex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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