Cavin-3 dictates the balance between ERK and Akt signaling.
Cavin-3 dictates the balance between ERK and Akt signaling.
复制标题
Cavin-3决定ERK和AKT信号传导之间的平衡。
DOI：
10.7554/elife.00905
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发表时间：
2013-09-24
期刊：
影响因子：
7.7
通讯作者：
Michaely P
中科院分区：
文献类型：
--
作者：
Hernandez VJ;Weng J;Ly P;Pompey S;Dong H;Mishra L;Schwarz M;Anderson RG;Michaely P
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 The plasma membrane separates cells from their environment, and surface receptors in this membrane allow cells to respond to changes in their environment by converting external cues into intracellular signals. This process, which is known as signal transduction, plays a central role in the biology of cells, and abnormal signaling is a common cause of human disease. In cancer for example, signals tend to be too strong or they are sent at the wrong time. Signal transduction frequently occurs at specialized regions of the plasma membrane. Caveolae are small indentations of the plasma membrane that comprise one type of signaling specialization. A protein that is concentrated in caveolae, cavin-3, suppresses tumor formation and is commonly absent from cancer cells. These observations suggest that cavin-3 participates in signal transduction and pathways that are associated with cancer, but the details of this involvement are not well understood. Hernandez et al. now show that cavin-3 controls the balance between two key intracellular signals, ERK and Akt. High levels of cavin-3 promote activation of the ERK signaling pathway but suppress activation of the Akt signaling pathway. Loss of cavin-3 has the opposite effect, activating Akt at the expense of ERK. The consequences of loss of cavin-3 include accelerated cell proliferation, the induction of Warburg metabolism (a metabolic state that supports rapid cell division), and the suppression of the apoptosis pathway. (Suppression of this pathway, which leads to cell death, allows cancer cells to proliferate in the body.) While deletion of the cavin-3 gene in mice is not sufficient to cause spontaneous cancer, animals that are deficient in cavin-3 die prematurely of cachexia, a tissue wasting sequela experienced by nearly half of all cancer patients. Hernandez et al. also show that cavin-3 influences cellular signaling by linking caveolae to the membrane skeleton—a network of proteins that underlies the plasma membrane. This linkage is necessary to ensure that cells have the correct abundance of caveolae, and it also facilitates signal transduction to the ERK signaling pathway. ERK activation in this context drives expression of two proteins, EGR1 and PTEN, which suppress Akt signaling. Hernandez et al. propose that the membrane skeleton functions as a scaffold that adaptors, such as cavin-3, use to assemble signaling modules with surface receptors for the purpose of controlling the signal transduction output from these receptors. DOI: http://dx.doi.org/10.7554/eLife.00905.002
