Decoding the Phosphatase Code: Regulation of Cell Proliferation by Calcineurin

Abstract

Calcineurin, a calcium-dependent serine/threonine phosphatase, integrates the alterations in intracellular calcium levels into downstream signaling pathways by regulating the phosphorylation states of several targets. Intracellular Ca²⁺ is essential for normal cellular physiology and cell cycle progression at certain critical stages of the cell cycle. Recently, it was reported that calcineurin is activated in a variety of cancers. Given that abnormalities in calcineurin signaling can lead to malignant growth and cancer, the calcineurin signaling pathway could be a potential target for cancer treatment. For example, NFAT, a typical substrate of calcineurin, activates the genes that promote cell proliferation. Furthermore, cyclin D1 and estrogen receptors are dephosphorylated and stabilized by calcineurin, leading to cell proliferation. In this review, we focus on the cell proliferative functions and regulatory mechanisms of calcineurin and summarize the various substrates of calcineurin. We also describe recent advances regarding dysregulation of the calcineurin activity in cancer cells. We hope that this review will provide new insights into the potential role of calcineurin in cancer development.

Keywords: calcineurin; cancer; cell cycle; dephosphorylation; intracellular calcium ions.

Figure 1

Regulation of cell cycle progression by calcineurin and CaMK. CaN dephosphorylates the NFAT transcription factor, which in turn activates p21, cyclin D1, CDK4, c-myc, and cyclin A. CaN also stabilizes cyclin D1 by dephosphorylation. Furthermore, the CaN/NFAT pathway and its downstream target c-myc regulate p21. p21 is a well-known inhibitor of CDK2-cyclin E and CDK4/6-cyclin D. CaMK negatively regulates the expression of p27, which is an inhibitor of CDK4-cyclin D and CDK2-cyclin E. CDK2-cyclin E and CDK4/6-cyclin D complexes phosphorylate Rb, leading to the activation of E2F1 and the subsequent G1/S progression. In G2/M, CaMK phosphorylates and activates cdc25, leading to downstream dephosphorylation and the activation of CDK1. Solid red lines indicate phosphorylation, red dotted lines indicate dephosphorylation, and green dotted lines indicate transcriptional activation.

Figure 2

A new role of calcineurin in cell proliferation. (a) CaN regulates the stability and transcription of Cyclin D1. Phosphorylation of Thr286 of cyclin D1 promotes polyubiquitination and the subsequent degradation of cyclin D1. CaN stabilizes cyclin D1 by dephosphorylating the Thr286 of cyclin D1. Furthermore, NFAT activated by CaN induces the transcription of cyclin D1. Thus, CaN contributes to cancer cell proliferation by regulating the stability and transcription of cyclin D1. (b) Calcineurin regulates the stability and activity of Erα. Phosphorylation of Ser294 of ERα promotes polyubiquitination by the E3 ligase E6AP and the subsequent degradation of ERα. By dephosphorylating the Ser294 of ERα, CaN releases E6AP from ERα and stabilizes ERα (left). Furthermore, CaN activates the Akt-mTOR pathway via the phosphorylation of Ser118 of ERα (right). Thus, CaN contributes to the proliferation of cancer cells by regulating the stability and activity of ERα.