Abstract
Loss of cell polarity impairs organ development and function; it can also serve as one of the first triggers for oncogenesis. In 2006-2007 two groups simultaneously reported the existence of a special pathway for maintaining epithelial polarity in the face of environmental stressors. In this pathway, AMPK, a key sensor of metabolic stress stabilizes tight junctions, preserves cell polarity, and thereby, maintains epithelial barrier functions. Accumulating evidence since has shown that pharmacologic activation of AMPK by Metformin protects the epithelial barrier against multiple environmental and pathological stressful states and suppresses tumorigenesis. How AMPK protects the epithelium remained unknown until recently Aznar et al. identified GIV/Girdin as a novel effector of AMPK at the cell-cell junctions; phosphorylation of GIV at a single site by AMPK appears to be both necessary and sufficient for strengthening tight junctions and preserving cell polarity and epithelial barrier function in the face of energetic stress. Here we review the fundamentals of this specialized signaling pathway that buttresses cell-cell junctions against stress-induced collapse and discuss its pathophysiologic relevance in the context of a variety of diseases, including cancers, diabetes, aging, and the growing list of beneficial effects of the AMPK-activator, Metformin.
Highlights
Epithelial cells usually display a polarized organization such that, localization of membrane proteins and positioning of organelles differ between the apical and basolateral sides of the cell [1]
It is because of its ability to couple energy sensing to cell polarity, activation of AMPactivated protein kinase (AMPK) was critical for protecting cell junctions against stressinduced collapse
The catalytic activity of AMPK is critical because either depletion of the AMPK catalytic α-subunit or expression of a kinase-dead mutant of AMPK inhibits tight junction (TJ) assembly as indicated by a loss of transepithelial electrical resistance (TEER); the latter is a measure of paracellular ion flow which depends on TJ stability
Summary
Epithelial cells usually display a polarized organization such that, localization of membrane proteins and positioning of organelles differ between the apical and basolateral sides of the cell [1]. A recent study [34] demonstrated that GIV (G-alpha interacting vesicle associated protein, a.k.a. Girdin), a multimodular polarity scaffold protein is a novel substrate of AMPK, and defined the molecular mechanisms by which the AMPK-GIV signaling axis protects the epithelium by stabilizing TJs and preserving cell polarity when challenged with energetic stress.
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