Mst4 and Ezrin Induce Brush Borders Downstream of the Lkb1/Strad/Mo25 Polarization Complex

Hubrecht Institute, KNAW and University Medical Centre, Utrecht, The Netherlands.
Developmental Cell (Impact Factor: 9.71). 05/2009; 16(4):551-62. DOI: 10.1016/j.devcel.2009.01.016
Source: PubMed


The human Lkb1 kinase, encoded by the ortholog of the invertebrate Par4 polarity gene, is mutated in Peutz-Jeghers cancer syndrome. Lkb1 activity requires complex formation with the pseudokinase Strad and the adaptor protein Mo25. The complex can induce complete polarization in a single isolated intestinal epithelial cell. We describe an interaction between Mo25alpha and a human serine/threonine kinase termed Mst4. A homologous interaction occurs in the yeast Schizosaccharomyces pombe in the control of polar tip growth. Human Mst4 translocates from the Golgi to the subapical membrane compartment upon activation of Lkb1. Inhibition of Mst4 activity inhibits Lkb1-induced brush border formation, whereas other aspects of polarity such as the formation of lateral junctions remain unaffected. As an essential event in brush border formation, Mst4 phosphorylates the regulatory T567 residue of Ezrin. These data define a brush border induction pathway downstream of the Lkb1/Strad/Mo25 polarization complex, yet separate from other polarity events.

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    • "In addition, we found that phosphorylated ezrin was almost completely within the actin cap at the cathode side of LS174T- W4 cells exposed to the electric field plus Dox, but there was no actin and ezrin cap formation in control cells (Fig. 2F). This suggests that an applied electric field not only promotes the polarization of actin, but also activates and polarizes ezrin, which is a key molecule in the polarization of intestinal epithelial cells (ten Klooster et al., 2009). ERK1/2 mediates electric field-induced activation of LKB1 "
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    • "PDZGEFs have been recently identified as the GEFs responsible for the activation of Rap2a during brush border formation [5]. Establishment of intestinal epithelial polarity requires the formation of a polarization complex composed of the protein kinase Lkb1, the pseudo-kinase STRADα and the adaptor protein Mo25 [9], [10]. This results in establishment of apico-basal polarity and asymmetric distribution of polarity landmarks, such as accumulation of PtdIns(4,5)P2 at the apical membrane. "
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    • "Lkb1 is best known for its ability to phosphorylate and activate AMP kinase (AMPK) as part of a sensing mechanism of cellular energy status with inputs into metabolic pathways and mTOR activity (Hawley et al., 2003; Lizcano et al., 2004; Shaw et al., 2004). Although these two components themselves have been linked to a variety of additional functions such as adhesion, proliferation , and polarity, Lkb1 likely has several additional relevant targets (Baas et al., 2004; Lee et al., 2007; Mirouse et al., 2007; ten Klooster et al., 2009). For example, Par-1 is the Lkb1 target in the C. elegans embryo that contributes to defining its posterior domain (Kemphues et al., 1988), and MARK2, the Par-1 mammalian homologue, is targeted by an Helicobacter pylori virulence factor to disrupt epithelial polarity (Saadat et al., 2007). "
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