Complete Polarization of Single Intestinal Epithelial Cells upon Activation of LKB1 by STRAD

Abstract

The LKB1 gene encodes a serine/threonine kinase that is mutated in the Peutz-Jeghers cancer syndrome. LKB1 is homologous to the Par-4 polarity genes in C. elegans and D. melanogaster. We have previously reported the identification and characterization of an LKB1-specific adaptor protein, STRAD, which activates LKB1 and translocates it from nucleus to cytoplasm. We have now constructed intestinal epithelial cell lines in which inducible STRAD activates LKB1. Upon LKB1 activation, single cells rapidly remodel their actin cytoskeleton to form an apical brush border. The junctional proteins ZO-1 and p120 redistribute in a dotted circle peripheral to the brush border, in the absence of cell-cell contacts. Apical and basolateral markers sort to their respective membrane domains. We conclude that LKB1 can induce complete polarity in intestinal epithelial cells. In contrast to current thinking on polarization of simple epithelia, these cells can fully polarize in the absence of junctional cell-cell contacts.

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

“…Several previous studies already demonstrated the requirement of LKB1 and JNK for epithelial integrity and polarity, both in the mammalian and Drosophila systems. 21,22,27,57 Consistently, we observed that inhibition of LKB1 activity during development caused various morphogenesis defects including malformation of adult thoraxes and failure in embryonic dorsal closure. Furthermore, we also showed that LKB1 is required for maintaining adequate JNK activity during embryonic and larval development.…”

“…19,20 Finally, LKB1 was shown to be necessary for the polarization of intestinal epithelial cells and Drosophila ovary cells, demonstrating another important function of LKB1 in regulating cell structure. 21,22 Although considerable progress has been made to characterize the in vivo function of LKB1, only a limited amount of information concerning its molecular mechanisms has been found in detail; the major biological pathway responsible for the tumor suppressive function of LKB1 remains to be clarified.…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…These observations indicate that LKB1 is a tumor suppressor acting upstream of PAR1. Indeed, LKB1 is a mammalian ortholog of C. elegans PAR4 and is involved in polarity regulation in mammalian cells (Baas et al, 2004). The causal link between LKB1 and the cancer-prone PeutzJeghers syndrome supports the idea that defects in epithelial polarity are required for the development of epithelial tumors.…”

LKB1; linking cell structure and tumor suppression

“…(1) remodeling of the actin cytoskeleton to an apical brush border, (2) relocalization of zona occludens 1 and p120-catenin to form junctional complexes and (3) the sorting of surface proteins to apical and basolateral domains (Baas et al, 2004a). LKB1 can also regulate the polarization of lung cancer cell lines in association with recruitment of the small GTPase, Cdc42, a known regulator of cell polarity see Etienne-Manneville, 2008).…”

“…Kinase-dead mutants of LKB1 are incapable of inducing polarity in Drosophila and in mammalian intestinal epithelial cells indicating that LKB1 catalytic function is required (Forcet et al, 2005). In addition, mammalian cells require STRAD-mediated translocation of LKB1 from the nucleus to the cytoplasm (Baas et al, 2004a). Beyond these general features, it is likely the LKB1 controls cell polarity in a cell type-specific manner with different contributions from individual AMPK family members.…”