Sann-Joong-Kuey-Jian-Tang induces autophagy in HepG2 cells via regulation of the phosphoinositide-3 kinase/Akt/mammalian target of rapamycin and p38 mitogen-activated protein kinase pathways

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.

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Dual Inhibition of Mitogen-Activated Protein Kinase and Mammalian Target of Rapamycin in Differentiated and Anaplastic Thyroid Cancer

Endocrine Reviews ◽

10.1210/edrv.30.6.9995 ◽

2009 ◽

Vol 30 (6) ◽

pp. 746-746

Keyword(s):

Thyroid Cancer ◽

Protein Kinase ◽

Mammalian Target Of Rapamycin ◽

Anaplastic Thyroid Cancer ◽

Mitogen Activated Protein Kinase ◽

Target Of Rapamycin ◽

Mitogen Activated Protein ◽

Dual Inhibition

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

Biochemical Journal ◽

10.1042/bj20041058 ◽

2004 ◽

Vol 384 (3) ◽

pp. 489-494 ◽

Cited By ~ 33

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.

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Mammalian Tribbles Homologs at the Crossroads of Endoplasmic Reticulum Stress and Mammalian Target of Rapamycin Pathways

Scientifica ◽

10.1155/2013/750871 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 11

Author(s):

Robyn Cunard

Keyword(s):

Protein Kinase ◽

Treatment Options ◽

Expression Patterns ◽

Mammalian Target Of Rapamycin ◽

Family Members ◽

Mitogen Activated Protein Kinase ◽

Target Of Rapamycin ◽

Glucose And Lipid Metabolism ◽

Mitogen Activated Protein ◽

Drosophila Protein

In 2000, investigators discovered Tribbles, a Drosophila protein that coordinates morphogenesis by inhibiting mitosis. Further work has delineated Xenopus (Xtrb2), Nematode (Nipi-3), and mammalian homologs of Drosophila tribbles, which include TRB1, TRB2, and TRB3. The sequences of tribbles homologs are highly conserved, and despite their protein kinase structure, to date they have not been shown to have kinase activity. TRB family members play a role in the differentiation of macrophages, lymphocytes, muscle cells, adipocytes, and osteoblasts. TRB isoforms also coordinate a number of critical cellular processes including glucose and lipid metabolism, inflammation, cellular stress, survival, apoptosis, and tumorigenesis. TRB family members modulate multiple complex signaling networks including mitogen activated protein kinase cascades, protein kinase B/AKT signaling, mammalian target of rapamycin, and inflammatory pathways. The following review will discuss metazoan homologs of Drosophila tribbles, their structure, expression patterns, and functions. In particular, we will focus on TRB3 function in the kidney in podocytes. This review will also discuss the key signaling pathways with which tribbles proteins interact and provide a rationale for developing novel therapeutics that exploit these interactions to provide better treatment options for both acute and chronic kidney disease.

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