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Review
. 2018 Jun 4;19(6):1657.
doi: 10.3390/ijms19061657.

Some Biological Consequences of the Inhibition of Na,K-ATPase by Translationally Controlled Tumor Protein (TCTP)

Jiwon Jung  1 , Seonhyung Ryu  2 , In A Ki  3 , Hyun Ae Woo  4 , Kyunglim Lee  5
Affiliations
Review

Some Biological Consequences of the Inhibition of Na,K-ATPase by Translationally Controlled Tumor Protein (TCTP)

Jiwon Jung et al. Int J Mol Sci. .

Abstract

Na,K-ATPase is an ionic pump that regulates the osmotic equilibrium and membrane potential of cells and also functions as a signal transducer. The interaction of Na,K-ATPase with translationally controlled tumor protein (TCTP) results, among others, in the inhibition of the former's pump activity and in the initiation of manifold biological and pathological phenomena. These phenomena include hypertension and cataract development in TCTP-overexpressing transgenic mice, as well as the induction of tumorigenesis signaling pathways and the activation of Src that ultimately leads to cell proliferation and migration. This review attempts to collate the biological effects of Na,K-ATPase and TCTP interaction and suggests that this interaction has the potential to serve as a possible therapeutic target for selected diseases.

Keywords: Na,K-ATPase; autophagy; hypertension; translationally controlled tumor protein; tumorigenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms behind hypertension and cataract in TCTP-overexpressing transgenic mice. Systemic arterial hypertension and cataract are induced through the inhibition of Na,K-ATPase, which leads to accumulation of Na+ and increase in cytoplasmic Ca2+ mobilization. Increased Ca2+ levels in sarcoplasmic reticulum and endoplasmic reticulum(S/ER) cause an increase in vascular smooth muscle contractility, inducing hypertension. In lens epithelial cells, the increased Ca2+ mobilization activates proteolytic enzymes that cause apoptosis and cataract. (formula image, Na+; formula image Ca2+; formula image, proteolytic enzymes).
Figure 2
Figure 2
A schematic overview of TCTP-induced Na,K-ATPase signaling pathways. (A) PI3K p85 subunit and Src are constitutively bound to Na,K-ATPase α subunit in the normal state; (B) When TCTP is overexpressed, TCTP interacts with Na,K-ATPase α subunit and induces Na,K-ATPase conformational changes that result in Src and p85 release. Activated Src transactivates PI3K–AKT, Ras–Raf–MEK–ERK1/2, Rac–PAK1/2, MKK3/6–p38 and phospholipase C (PLC)-γ signaling pathways. TCTP enhances NADPH oxidase-dependent reactive oxygen species (ROS) and induces matrix metalloproteinase (MMP)-3 and -13.
Figure 3
Figure 3
TCTP as a negative regulator of autophagy. TCTP negatively regulates AMPK, which leads to mTORC1 activation that promotes cell proliferation and inhibits autophagy in HeLa cells. TCTP also inhibits MAPK8–JNK1 which is known to phosphorylate and degrade BCL2. BCL2 forms a complex with BECN1 in the normal state, inhibiting autophagy. Once BCL2 is phosphorylated and degraded upon stress or starvation, BECN1 forms a complex with class III PI3K and UV radiation resistance-associated gene (UVRAG) and induces autophagy.
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