LKB1 and AMPK in cell polarity and

LKB1 and AMP-activated protein kinase (AMPK) areserine–threonine kinases implicated in key cellular path-ways, including polarity establishment and energy sen-sing, respectively. Recent in vivo analyses in DrosophilahavedemonstratedvitalrolesforbothAMPKandLKB1–inpartthroughthemyosinregulatorylightchain–incellpolarity and cell division. Evidence from mammalianexperiments also supports non-metabolic functions forLKB1 and AMPK. This review examines unanticipatedAMPK functions for initiating and maintaining cellpolarity and completing normal cell division. The abilityof AMPK to sense energy status might be coupled withfundamental cell biological functions.IntroductionAMP-activated protein kinase (AMPK) is a serine–thero-nine kinase involved in the regulation of cell metabolism(forreview,see[1]). AMPKisoftenreferredtoasan‘energysensor’, because its activity increases with cellular stres-sors, particularly those that decrease ATP levels whileincreasing AMP:ATP ratios. In response, activated AMPKthen turns on ATP-generating pathways while inhibitingATP-consuming pathways, thereby increasing ATP:AMPratios [2–5]. AMPK consists of a heterotrimeric proteincomplex with a catalytic subunit, a, and two regulatorysubunits, b and g (Box 1) [2–15]. AMPK catalytic andregulatory subunits are highly conserved, with orthologsexpressed in plants, yeast, Drosophila, Caenorhabditiselegans, vertebrates and mammals [2–5]. However, theﬁrst mutations in an AMPK complex gene were identiﬁedas mutations in Snf1 (sucrose non-fermenting 1) proteinkinase, the Saccharomyces cerevisiae ortholog of AMPKa[2,4,5,7,16–18]. The LKB1 serine–threonine kinase has most often beenstudied as a signaling molecule in cell polarity; however, arecent study identiﬁed potential metabolic roles for LKB1as a potential partial mediator of the type 2 diabetes drugmetformin [19]. LKB1 is the most characterized upstreamactivating kinase for AMPK. Several other AMPK activa-tors [20–35] and mechanisms [36–38] have been described(Box 2). LKB1 phosphorylates a conserved threonine(T172) within the T-loop of AMPKa, leading to its acti-vation[39,40]. WhenLKB1isnotpartofthecomplex,itcanbe localized to the nucleus. Translocation to the cytoplasmoccurs as the LKB1–STRAD (STE20-related adaptor)–MO25 (mouse protein 25) complex is assembled [39–44]. LKB1 also contains a conserved C-terminal CaaX-likemotif, allowing for possible prenylation and membraneassociation as well [45–47]; however, LKB1 is not knownto be asymmetrically localized on the plasma membrane.Recent studies indicate that LKB1 mutations causePeutz-Jeghers syndrome, with increased risk of lung ade-nocarcinoma, cervical carcinoma, and breast cancer [48–53], suggesting a tumor suppressor role for LKB1. Insupportof this,LKB1hasbeenshown toinhibit themTOR(mammalian target of rapamycin) pathway and to interactwith p53 to mediate p53-dependent apoptosis [40,48,52–55]. In addition to its involvement in energy metabolism,LKB1 has the capacity to regulate multiple cellular pro-cesses, such as cell cycle arrest, Wnt signaling, transform-ing growth factor beta (TGF-b) signaling and chromatinremodeling [40,54]. C. elegans Par-4 (the ortholog of LKB1) was originallyisolated as a mutant affecting cellular asymmetry andpolarity. The C. elegans and Drosophila genomes eachencode one LKB1 gene – PAR4 and dLKB1, respectively.Recent investigation has conﬁrmed that the originallyidentiﬁedfunctionsforLKB1inC. elegans–ascellpolarityregulators [56] – are conserved in mammalian orthologs.Furthermore, recent studies have also identiﬁed newAMPK functions in coordinating energy status with reg-ulating cell polarity and/or cell division. In this review, wefocus on the non-metabolic functions of the LKB1–AMPKsignaling module in regulating cell polarity.LKB1 function in cell polarityEstablishing and maintaining proper cell polarity are keyaspects of multicellular development, whether for gener-ating the initial embryo pattern during development or formaintaining cellular and tissue function in the adult.Numerous contextual cues aid polarity establishmentand maintenance. These cues include cell–cell inter-actions, intracellular transport, membrane homeostasis,and cellular signaling responses to external cues. Loss ofpolarized cellular traits often characterizes epithelial-derived tumors, which are otherwise highly polarized celltypes. DrosophilaLKB1wasidentiﬁedfromageneticscreentoidentify mutations that affect oocyte cell polarity [45]. Aswith mutants of the PAR-4 C. elegans counterpart,mutants of Drosophila LKB1 display disrupted polarityand disrupted anterior–posterior (A–P) patterning. Toidentify additional genes involved in A–P axis formationin Drosophila, a genetic screen was conducted in germlineclones for mutants that disrupt the localization of Staufen.The screen was able to identify LKB1 mutant clones that