SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells
Joshua A. Mason, Jordan A. Cockfield, Daniel J. Pape, Hannah Meissner, Michael T. Sokolowski, Taylor C. White, José C. Valentín López, Juan Liu, Xiaojing Liu, Inmaculada Martínez‐Reyes, Navdeep S. Chandel, Jason W. Locasale, Zachary T. Schafer
Abstract
Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that affect cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM detachment. In addition, loss of ECM attachment causes profound alterations in cellular metabolism, which can lead to anoikis-independent cell death. Here, we describe a surprising role for serum and glucocorticoid kinase-1 (SGK1) in the promotion of energy production when cells are detached. Our data demonstrate that SGK1 activation is necessary and sufficient for ATP generation during ECM detachment and anchorage-independent growth. More specifically, SGK1 promotes a substantial elevation in glucose uptake because of elevated GLUT1 transcription. In addition, carbon flux into the pentose phosphate pathway (PPP) is necessary to accommodate elevated glucose uptake and PPP-mediated glyceraldehyde-3-phosphate (G3P) is necessary for ATP production. Thus, our data show SGK1 as master regulator of glucose metabolism and cell survival during ECM-detached conditions.