Trends in Cell Biology
LKB1 tumor suppressor protein: PARtaker in cell polarity
Section snippets
LKB1 homologs in mice, worms and flies
To study the role of LKB1 in vivo, the murine Lkb1 gene was disrupted by four independent groups 13, 14, 15, 16, 17. Lkb1−/− mice die at midgestation and display numerous abnormalities, including neural tube defects and severely impaired vascular development. Lkb1+/− mice are viable, fertile and appear to be healthy at birth and during early adult life. At later ages, the heterozygous mice develop PJS-like hamartomatous polyps in the stomach and small intestine. It is not entirely clear whether
LKB1 as a regulator of multiple cellular processes
Molecular and biochemical studies over the past six years have implicated LKB1 in a broad range of cellular processes, including the control of cell-cycle arrest [22], p53-mediated apoptosis [23], Wnt signaling 24, 25, transforming growth factor (TGF)-β signaling [26], ras-induced cell transformation [14], and energy metabolism 27, 28, 29. A G1 cell-cycle arrest was observed upon forced expression of LKB1 in melanoma cells (G361) that lack endogenous LKB1 [22]. This G1-arrest was later found to
LKB1 is activated in a trimeric complex
In 2003, in collaboration with Dario Alessi and colleagues, we discovered that endogenous LKB1 requires two other proteins for correct localization and kinase activity: STE20-related adaptor (STRAD) and MO25 35, 36. Both STRAD and MO25 exist as two isoforms, encoded by the closely related genes STRADα and STRADβ (also known as ILPIP and PAP-kinase 37, 38) and MO25α and MO25β, respectively. The STRAD proteins are members of the STE20-like kinase family, originally identified in yeast. Mammalian
LKB1 as an upstream activator of AMPK/PAR1-related kinases
Following the identification of active LKB1–STRAD–MO25 complexes, three independent groups recently reported LKB1 as the upstream kinase of the key metabolic regulator 5′-AMP-activated protein kinase (AMPK) 27, 28, 29. AMPK is activated during metabolic stress, when cellular AMP:ATP ratios rise, and regulates multiple processes to re-establish the energy charge of the cell [42]. LKB1 was shown to activate AMPK by phosphorylating Thr172 in the regulatory activation loop, or T-loop, a distinct
Control of cell polarity by the PAR proteins in C. elegans and D. melanogaster
The establishment and maintenance of polarity are crucial during development, to specify cell fate, and to accomplish various cellular functions. Genetic screens in C. elegans have revealed a set of six unrelated PAR genes 20, 51, 52. A comparison of the PAR homologs of C. elegans, D. melanogaster and mammals is provided in Table 1. All six PAR proteins are required for proper execution of the first two asymmetric cell divisions of the C. elegans zygote (Figure 2a) [53]. Loss-of-function
Control of cell polarity by the PAR proteins in epithelial mammalian cells
Although most of the studies on polarity have been conducted in the model organisms C. elegans and D melanogaster, the molecular mechanism required to establish polarity in mammalian epithelial cells is now rapidly emerging. Not surprisingly, the key regulators of cell polarity in C. elegans and D melanogaster are implicated in the mammalian process (Figure 2b) [9]. Cell–extracellular matrix (ECM) contacts and cell–cell contacts are believed to be the spatial cues that lead to the transition of
LKB1 and cell polarity
Somewhat surprisingly, a large body of studies on LKB1, the mammalian PAR4 homolog, did not unveil a role for LKB1 in the establishment of polarity. However, utilizing STRAD as an essential coactivator facilitated the investigation of the cellular functions of LKB1. Activation of LKB1 by induced expression of STRAD in intestinal epithelial cells was recently shown to lead to the rapid cell-autonomous execution of a complete polarization program [12]. Within hours of activating LKB1, the actin
Concluding remarks
Over the past six years, the LKB1 tumor suppressor kinase has been extensively studied and implicated in a variety of cellular processes. Most recently, LKB1 was described as a ‘master’ regulator of cell polarity [12], in line with the roles of LKB1 homologs in C. elegans and D. melanogaster 19, 21. Based on an integration of various studies, we propose the following model for control of mammalian cell polarity by the interconnective PAR protein network (Figure 4). PAR4/LKB1 resides at the top
Acknowledgments
We thank Rachel Giles for critical reading of the manuscript, and Johan Offerhaus for helpful discussions. We also thank Jeroen Kuipers and Dario Alessi for help with figure preparation. Our work is supported by the Center for Biomedical Genetics.
References (92)
Very high risk of cancer in familial Peutz-Jeghers syndrome
Gastroenterology
(2000)Germline and somatic mutations of the STK11/LKB1 Peutz Jeghers gene in pancreatic and biliary cancers
Am. J. Pathol.
(1999)Tumor suppressors: linking cell polarity and growth control
Curr. Biol.
(2000)Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD
Cell
(2004)Identification of genes required for cytoplasmic localization in early C. elegans embryos
Cell
(1988)The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death
Mol. Cell
(2001)LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Curr. Biol.
(2003)LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest
J. Biol. Chem.
(2001)Interaction of activator of G-protein signaling 3 (AGS3) with LKB1, a serine/threonine kinase involved in cell polarity and cell cycle progression: phosphorylation of the G-protein regulatory (GPR) motif as a regulatory mechanism for the interaction of GPR motifs with Gi alpha
J. Biol. Chem.
(2003)ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis
J. Biol. Chem.
(2002)
Identification and characterization of a novel Ste-20/GCK-related kinase, PAP kinase (PAPK)
J. Biol. Chem.
The Ste20 group kinases as regulators of MAP kinase cascades
Trends Cell Biol.
Management of cellular energy by the AMP-activated protein kinase system
FEBS Lett.
Characterization of the AMP-activated protein kinase kinase from rat liver, and identification of threonine-172 as the major site at which it phosphorylates and activates AMP-activated protein kinase
J. Biol. Chem.
Kinase phosphorylation: keeping it all in the family
Curr. Biol.
Par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed
Cell
The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole
Cell
MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption
Cell
The Caenorhabditis elegans par-5 gene encodes a 14-3-3 protein required for cellular asymmetry in the early embryo
Dev. Biol.
Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos
Cell
Control of spindle orientation in Drosophila by the Par-3-related PDZ-domain protein Bazooka
Curr. Biol.
Drosophila 14-3-3/PAR-5 is an essential mediator of PAR-1 function in axis formation
Dev. Cell
Intercellular junctions and cellular polarity: the PAR-aPKC complex, a conserved core cassette playing fundamental roles in cell polarity
Curr. Opin. Cell Biol.
Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells
Cell
Origins of cell polarity
Cell
Classical cadherins
Semin. Cell Biol.
Assembly of tight junctions during early vertebrate development
Semin. Cell Dev. Biol.
Assembly of epithelial tight junctions is negatively regulated by Par6
Curr. Biol.
Mammalian homologues of C. elegans PAR-1 are asymmetrically localized in epithelial cells and may influence their polarity
Curr. Biol.
Apical surface formation in MDCK cells: regulation by the serine/threonine kinase EMK1
Methods
Phosphorylation-dependent binding of 14-3-3 to the polarity protein Par3 regulates cell polarity in mammalian epithelia
Curr. Biol.
PARsing embryonic polarity
Cell
On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentation of the skin and mucous membranes
Ned. Tijdschr. Geneeskd.
Generalised intestinal polyposis and melanin spots of oral mucosa, lips and digits: a syndrome of diagnostic significance
N. Engl. J. Med.
A serine/threonine kinase gene defective in Peutz-Jeghers syndrome
Nature
Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase
Nat. Genet.
Somatic mutations of the Peutz-Jeghers gene in malignant melanoma
Oncogene
Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung
Cancer Res.
Establishing cell polarity in development
Nat. Cell Biol.
Epithelial-mesenchymal transitions in tumour progression
Nat. Rev. Cancer
Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice
Science
Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation
Nature
Role of Lkb1, the causative gene of Peutz-Jeghers syndrome, in embryogenesis and polyposis
Proc. Natl. Acad. Sci. U. S. A.
Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice
Cancer Res.
Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis
Proc. Natl. Acad. Sci. U. S. A.
Hepatocellular carcinoma caused by loss of heterozygosity in lkb1 gene knockout mice
Cancer Res.
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