The stress polarity pathway: AMPK 'GIV'-es protection against metabolic insults

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.

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

“…The intestinal barrier is the largest mucosal surface that separates diverse stressors (trillions of microbes, toxins, and food antigens) on one side from the largest immune system on the other. A compromised gut barrier allows microbes and unwanted antigens to cross the epithelium and generate inflammation (systemic endotoxemia), which may contribute to a variety of diseases, ranging from metabolic syndrome and chronic organ dysfunctions to neurodegenerative diseases and cancers (Yacyshyn et al, 1996;Barbara, 2006;Camilleri & Gorman, 2007;Sandek et al, 2007Sandek et al, , 2008Sandek et al, , 2012Alam et al, 2014;Bischoff et al, 2014;Nouri et al, 2014;Samsam et al, 2014;van De Sande et al, 2014;Clairembault et al, 2015;Lee et al, 2015;Buscarinu et al, 2016;Xue et al, 2016;Ghosh, 2017). Evidence also shows that aging-related genes, that is, the sirtuins (SIRTs1, 3, 6), are critical for the integrity of the gut barrier and for controlling inflammation in the gut (Akimova et al, 2014;Akbulut et al, 2015;Liu et al, 2017b;Zhang et al, 2018).…”

“…Findings also reveal the therapeutic potential of AMPK agonists such as metformin in strengthening the gut barrier. Over the years, the beneficial (protective) effect of multiple nutritional components, dietary supplements, and pharmacologic agents, including the widely prescribed AMPK-activator, metformin, on intestinal permeability in health and disease has been investigated; all studies converge on AMPK activation as a common pre-requisite for rendering such protection (reviewed in (Ghosh (2017)). Taken together with these prior works, our findings provide an impetus for harnessing the diagnostic and therapeutic potential of the SPSpathway in the setting of a variety of diseases that are associated with increased intestinal permeability such as inflammaging and cancer.…”

Girdin is a component of the lateral polarity protein network restricting cell dissemination

“…In addition, it was demonstrated recently that GIRDIN acts as an effector of AMP-activated protein kinase (AMPK) under energetic stress to maintain tight junction function [39]. Of note, these two functions are not shared by fly Girdin [58,59], and were thus acquired by GIRDIN during evolution to fulfill specialized functions. In contrast, our discovery of the Girdin-dependent inhibition of aPKC reveals a core mechanism contributing to epithelial cell polarization from flies to humans.…”

Midgut Mitochondrial Function as a Gatekeeper for Malaria Parasite Infection and Development in the Mosquito Host

“…In more recent work, treatment with rapamycin, which inhibits Akt-dependent mechanistic Target of Rapamycin (mTOR) signaling, maintained epithelial barrier integrity and extended lifespan in D. melanogaster independently of any changes in the gut microbiota (Schinaman et al, 2019). In mammals, AMPK is required for regulation of polarity of hepatocytes and other epithelial cell types as well as tight junction and barrier integrity through increased mitochondrial fusion and biogenesis (Treyer and Müsch, 2013;Kang et al, 2016;Ghosh, 2017). Successful P.…”