scholarly journals p38 regulates the tumor suppressor PDCD4 via the TSC-mTORC1 pathway

Cell Stress ◽  
2021 ◽  
Vol 5 (12) ◽  
pp. 176-182
Author(s):  
Clarissa Braun ◽  
Karl Katholnig ◽  
Christopher Kaltenecker ◽  
Monika Linke ◽  
Nyamdelger Sukhbaatar ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tumor Suppressor ◽  
Mammalian Target Of Rapamycin ◽  
Nutrient Sensing ◽  
Mitogen Activated Protein Kinase ◽  
Pdcd4 Expression ◽  
Mitogen Activated Protein ◽  
Inflammatory Processes ◽  
Mtorc1 Pathway ◽  
Phosphoinositide 3 Kinase

Programmed cell death protein 4 (PDCD4) exerts critical functions as tumor suppressor and in immune cells to regulate inflammatory processes. The phosphoinositide 3-kinase (PI3K) promotes degradation of PDCD4 via mammalian target of rapamycin complex 1 (mTORC1). However, additional pathways that may regulate PDCD4 expression are largely ill-defined. In this study, we have found that activation of the mitogen-activated protein kinase p38 promoted degradation of PDCD4 in macrophages and fibroblasts. Mechanistically, we identified a pathway from p38 and its substrate MAP kinase-activated protein kinase 2 (MK2) to the tuberous sclerosis complex (TSC) to regulate mTORC1-dependent degradation of PDCD4. Moreover, we provide evidence that TSC1 and TSC2 regulate PDCD4 expression via an additional mechanism independent of mTORC1. These novel data extend our knowledge of how PDCD4 expression is regulated by stress- and nutrient-sensing pathways.

scholarly journals Identification of filamin C as a new physiological substrate of PKBα using KESTREL

2004 ◽  
Vol 384 (3) ◽  
pp. 489-494 ◽  
Author(s):  
James T. MURRAY ◽  
David G. CAMPBELL ◽  
Mark PEGGIE ◽  
Mora ALFONSO ◽  
Philip COHEN
Keyword(s):  
Protein Kinase ◽  
Cardiac Muscle ◽  
Mammalian Target Of Rapamycin ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Phosphoinositide 3 Kinase ◽  
Filamin C

We detected a protein in rabbit skeletal muscle extracts that was phosphorylated rapidly by PKBα (protein kinase Bα), but not by SGK1 (serum- and glucocorticoid-induced kinase 1), and identified it as the cytoskeletal protein FLNc (filamin C). PKBα phosphorylated FLNc at Ser2213in vitro, which lies in an insert not present in the FLNa and FLNb isoforms. Ser2213 became phosphorylated when C2C12 myoblasts were stimulated with insulin or epidermal growth factor, and phosphorylation was prevented by low concentrations of wortmannin, at which it is a relatively specific inhibitor of phosphoinositide 3-kinase. PD 184352 [an inhibitor of the classical MAPK (mitogen-activated protein kinase) cascade] and/or rapamycin [an inhibitor of mTOR (mammalian target of rapamycin)] had no effect. Insulin also induced the phosphorylation of FLNc at Ser2213 in cardiac muscle in vivo, but not in cardiac muscle that does not express PDK1 (3-phosphoinositide-dependent kinase 1), the upstream activator of PKB. These results identify the muscle-specific isoform FLNc as a new physiological substrate for PKB.

Parkinson´s related protein DJ-1 is involved in aberrant cell cycle re-entry through Cdk5

2020 ◽  
Author(s):  
Mª José López-Grueso ◽  
Carmen Alicia Padilla ◽  
José Antonio Bárcena ◽  
Raquel Requejo-Aguilar
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cortical Neurons ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoints ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Multifunctional Protein ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Abstract DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson´s disease remains elusive. Here, using a comparative proteomic analysis between normal cortical neurons and neurons lacking DJ-1, we show that this protein is involved in cell cycle checkpoints disruption as a consequence of increased amount of p-Tau and a-synuclein proteins, altered signalling pathways, as the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK), and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation and the establishment of synapses, but can also contribute to cell cycle progression, as in our case, in pathological conditions. In addition, we observed a decrease in proteasomal activity, probably due to Tau phosphorylation that can also lead to activation of mitogenic signalling pathways. Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1 associated PD. Thereby, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies.

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