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)