Cavin-3 dictates the balance between ERK and Akt signaling

Abstract

Cavin-3 is a tumor suppressor protein of unknown function. Using both in vivo and in vitro approaches, we show that cavin-3 dictates the balance between ERK and Akt signaling. Loss of cavin-3 increases Akt signaling at the expense of ERK, while gain of cavin-3 increases ERK signaling at the expense Akt. Cavin-3 facilitates signal transduction to ERK by anchoring caveolae to the membrane skeleton of the plasma membrane via myosin-1c. Caveolae are lipid raft specializations that contain an ERK activation module and loss of the cavin-3 linkage reduces the abundance of caveolae, thereby separating this ERK activation module from signaling receptors. Loss of cavin-3 promotes Akt signaling through suppression of EGR1 and PTEN. The in vitro consequences of the loss of cavin-3 include induction of Warburg metabolism (aerobic glycolysis), accelerated cell proliferation, and resistance to apoptosis. The in vivo consequences of cavin-3 knockout are increased lactate production and cachexia.DOI: http://dx.doi.org/10.7554/eLife.00905.001

Caveolae – mechanosensitive membrane invaginations linked to actin filaments

“…Recently, the motor protein myosin 1c (Myo1c) has also been suggested to have a role in mediating the association between caveolae and actin (Hernandez et al, 2013). Myo1c depletion induces a perinuclear accumulation of Cav1, which results in a decrease in caveolar density, a phenotype that is compatible with the described role of Myo1c in the recycling of lipid rafts (Brandstaetter et al, 2012).…”

“…Interestingly, Myo1c interacts with Cavin3, and the two proteins share a similar subcellular distribution ( Fig. 2) (Hernandez et al, 2013). However, whether Myo1c directly mediates the association between caveolae and stress fibers remains unclear.…”

“…Cavin1, in turn, interacts with either cavin2 or cavin3, but not with both at the same time (Ludwig et al, 2013;Gambin et al, 2014). Cavin2 has an important role in caveolae formation in certain tissues such as lung endothelium, whereas cavin3 appears to be important for caveolae formation in cell lines, but not in mice (Hansen et al, 2013;Hernandez et al, 2013). In addition to cavins, Pacsin2, an F-BAR protein involved in clathrin-mediated endocytosis, regulates caveolar shape (Hansen et al, 2011;Senju et al, 2011;Koch et al, 2012).…”

Cavin family proteins and the assembly of caveolae

“…Furthermore, in addition to the assembly of caveolae, understanding the mechanisms that control the dynamic disassembly of caveolae, and the subsequent redistribution and turnover of cavin proteins in response to stimuli -such as cholesterol depletion (Breen et al, 2012;Murata et al, 1995), signal transduction (Aboulaich et al, 2006), and membrane stress (Gambin et al, 2014;Sinha et al, 2011) -remains relatively unexplored. As a final comment, it is known that changes in microtubule and actin assembly can alter caveolar transport and stability (Hernandez et al, 2013;Mundy et al, 2002;Verma et al, 2010;Wickström et al, 2010) (reviewed in Parton anddel Pozo, 2013). Furthermore, caveolae are morphologically associated with cytoskeletal structures (Richter et al, 2008); however, it remains to be addressed whether interactions with cytoskeletal proteins have a direct role in caveolar biogenesis.…”

A Novel Inhibitor of AKT1–PDPK1 Interaction Efficiently Suppresses the Activity of AKT Pathway and Restricts Tumor Growth In Vivo

“…The screening experiments were performed in H1299 cells, which are known to harbor an active AKT signaling (23,24) and are well suited for experiments involving DNA transfection (Fig. 1B).…”