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

Authors:

Clarissa Braun1,2, Karl Katholnig1, Christopher Kaltenecker3, Monika Linke1, Nyamdelger Sukhbaatar1, Markus Hengstschläger1 and Thomas Weichhart1
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Affiliations:

1 Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.

2 Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

3 Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.

Keywords: 

macrophages, cancer, rapamycin, MK2, PDCD4, p38, mTORC1, TSC1, TSC2.

Abbreviations:

BMDM – bone marrow-derived macrophage;

CK2 – casein kinase 2;

LPS – lipopolysaccharide;

MAPK – mitogen-activated kinase;

MK2 – MAP kinase-activated protein kinase 2;

mTORC1 – mammalian target of rapamycin complex 1;

PDCD4 – programmed cell death protein 4;

PI3K – phosphoinositide 3-kinase;

RSK – ribosomal S6 kinase;

TSC – tuberous sclerosis complex.

Corresponding Author(s):

T. Weichhart, Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria; thomas.weichhart@meduniwien.ac.at

Conflict of interest statement:

The authors declare no conflicts of interest.

Please cite this article as:

Clarissa Braun, Karl Katholnig, Christopher Kaltenecker, Monika Linke, Nyamdelger Sukhbaatar, Markus Hengstschläger and Thomas Weichhart (2021). p38 regulates the tumor suppressor PDCD4 via the TSC-mTORC1 pathway. Cell Stress 5(12): 176-182. doi: 10.15698/cst2021.12.260

© 2021 Braun et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

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.