Abstract
The PAR-4 and PAR-1 kinases are necessary for the formation of the anterior–posterior (A–P) axis in Caenorhabditis elegans1,2,3. PAR-1 is also required for A–P axis determination in Drosophila4,5. Here we show that the Drosophila par-4 homologue, lkb1, is required for the early A–P polarity of the oocyte, and for the repolarization of the oocyte cytoskeleton that defines the embryonic A–P axis. LKB1 is phosphorylated by PAR-1 in vitro, and overexpression of LKB1 partially rescues the par-1 phenotype. These two kinases therefore function in a conserved pathway for axis formation in flies and worms. lkb1 mutant clones also disrupt apical–basal epithelial polarity, suggesting a general role in cell polarization. The human homologue, LKB1, is mutated in Peutz–Jeghers syndrome6,7 and is regulated by prenylation and by phosphorylation by protein kinase A8,9. We show that protein kinase A phosphorylates Drosophila LKB1 on a conserved site that is important for its activity. Thus, Drosophila and human LKB1 may be functional homologues, suggesting that loss of cell polarity may contribute to tumour formation in individuals with Peutz–Jeghers syndrome.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kemphues, K. J., Priess, J. R., Morton, D. G. & Cheng, N. S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988)
Watts, J. L., Morton, D. G., Bestman, J. & Kemphues, K. J. The C. elegans par-4 gene encodes a putative serine–threonine kinase required for establishing embryonic asymmetry. Development 127, 1467–1475 (2000)
Guo, S. & Kemphues, K. J. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81, 611–620 (1995)
Shulman, J. M., Benton, R. & St Johnston, D. The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 101, 377–388 (2000)
Tomancak, P. et al. A Drosophila melanogaster homologue of Caenorhabditis elegans par-1 acts at an early step in embryonic-axis formation. Nature Cell Biol. 2, 458–460 (2000)
Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998)
Jenne, D. E. et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nature Genet. 18, 38–43 (1998)
Collins, S. P., Reoma, J. L., Gamm, D. M. & Uhler, M. D. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem. J. 345, 673–680 (2000)
Sapkota, G. P. et al. Phosphorylation of the protein kinase mutated in Peutz–Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90RSK and cAMP-dependent protein kinase, but not its farnesylation at Cys433, is essential for LKB1 to suppress cell growth. J. Biol. Chem. 276, 19469–19482 (2001)
van Eeden, F. & St Johnston, D. The polarisation of the anterior–posterior and dorsal–ventral axes during Drosophila oogenesis. Curr. Opin. Genet. Dev. 9, 396–404 (1999)
St Johnston, D., Beuchle, D. & Nüsslein-Volhard, C. Staufen, a gene required to localize maternal RNAs in the Drosophila egg. Cell 66, 51–63 (1991)
Clark, I., Giniger, E., Ruohola-Baker, H., Jan, L. Y. & Jan, Y. L. Transient posterior localization of a kinesin fusion protein reflects anteroposterior polarity of the Drosophila oocyte. Curr. Biol. 4, 289–300 (1994)
Martin, S. G., Dobi, K. C. & St Johnston, D. A rapid method to map mutations in Drosophila. Genome Biol. 2, research0036.1–12 (2001)
Benton, R., Palacios, I. M. & St Johnston, D. Drosophila 14–3–3/PAR-5 is an essential mediator of PAR-1 function in axis formation. Dev. Cell 3, 659–671 (2002)
Spradling, A. The Development of Drosophila melanogaster (eds Bate, M. & Martinez-Arias, A.) 1–70 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1993)
Huynh, J. R., Shulman, J. M., Benton, R. & St Johnston, D. PAR-1 is required for the maintenance of oocyte fate in Drosophila. Development 128, 1201–1209 (2001)
Cox, D. N., Lu, B., Sun, T. Q., Williams, L. T. & Jan, Y. N. Drosophila par-1 is required for oocyte differentiation and microtubule organization. Curr. Biol. 11, 75–87 (2001)
de Cuevas, M. & Spradling, A. C. Morphogenesis of the Drosophila fusome and its implications for oocyte specification. Development 125, 2781–2789 (1998)
Rorth, P. Gal4 in the Drosophila female germline. Mech. Dev. 78, 113–118 (1998)
Lane, M. E. & Kalderon, D. RNA localization along the anteroposterior axis of the Drosophila oocyte requires PKA-mediated signal transduction to direct normal microtubule organization. Genes Dev. 8, 2986–2995 (1994)
Hemminki, A. The molecular basis and clinical aspects of Peutz–Jeghers syndrome. Cell. Mol. Life Sci. 55, 735–750 (1999)
Sanchez-Cespedes, M. et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659–3662 (2002)
Yoo, L. I., Chung, D. C. & Yuan, J. LKB1—a master tumour suppressor of the small intestine and beyond. Nature Rev. Cancer 2, 529–535 (2002)
Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002)
Xu, T. & Rubin, G. M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237 (1993)
Chou, T. B. & Perrimon, N. The autosomal FLP–DFS technique for generating germline mosaics in Drosophila melanogaster. Genetics 144, 1673–1679 (1996)
Sanson, B., White, P. & Vincent, J. P. Uncoupling cadherin-based adhesion from wingless signalling in Drosophila. Nature 383, 627–630 (1996)
Wodarz, A., Hinz, U., Engelbert, M. & Knust, E. Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila. Cell 82, 67–76 (1995)
Sun, T. Q. et al. PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nature Cell Biol. 3, 628–636 (2001)
Theurkauf, W. Drosophila melanogaster: Practical Uses in Cell and Molecular Biology (eds Goldstein, L. & Fyrberg, E.) 489–506 (Academic, London, 1994)
Acknowledgements
We thank M. Pal for fly injection; K. Litière for generating the kinesin–β-gal line; I. Palacios, B. Sanson, A. Wodarz and the Developmental Studies Hybridoma Bank for strains and antibodies; and J. Rouse, N. Lowe, J. Raff and R. Benton for advice and discussion. S.G.M. was supported by the Swiss National Science Foundation and D.StJ. by the Wellcome Trust.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Martin, S., St Johnston, D. A role for Drosophila LKB1 in anterior–posterior axis formation and epithelial polarity. Nature 421, 379–384 (2003). https://doi.org/10.1038/nature01296
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature01296
This article is cited by
-
The level of oncogenic Ras determines the malignant transformation of Lkb1 mutant tissue in vivo
Communications Biology (2021)
-
Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence
BMC Genomics (2018)
-
Controlling the master—upstream regulation of the tumor suppressor LKB1
Oncogene (2018)
-
Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner
Nature Communications (2018)
-
Molecular cloning, polymorphism, and expression analysis of the LKB1/STK11 gene and its association with non-specific digestive disorder in rabbits
Molecular and Cellular Biochemistry (2018)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.