Phosphatase Subfamily PPP3C

Phosphatase Classification: Fold MTDP: Superfamily MTDP: Family PPP: Subfamily PPP3C (PP2B, calcineurin)

PPP3C, the catalytic subunit of PP2B (calcineurin) holoeynzme, is a calcium-dependent serine/threonine phosphatase conserved in eukaryotes. It is involved in various biological processes and has significantly clinic relevance.

Evolution

PPP3C is found throughout eukaryotes, including opisthokonta, amoebazoa, plants and etc.

Domain

PPP3C has a single domain - phosphatase domain.

Functions

PPP3C is the catalytic subunit of Protein Phosphatase 2B (PP2B) holoenzyme (aka calcineurin). The holoenzyme is heterodimer complex consisting of one catalytic subunit and one regulatory subunit participates in very various cellular processes, from cell cycle progression to cardiac hypertrophy [1]. Below are some examples of its function:

• PP2B (calcineurin) activates the T cells of the immune system in mammals. When an antigen-preseting cell interacts with a T cell receptor on T cells, the cytoplasmic level of calcium increases, which activates calcineurin. PP2B (calcineurin) is used as a target for several immunosuppressive drugs, e.g. tacrolimus which is an immunosuppressive drug used mainly after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection [2].

• PP2B (calcineurin) is included as a key player in mediating calcium-triggered and -accelerated vesicle endocytosis [3].

• PP2B (calcineurin) activates a vertebrate-specific transcription factor called NFATc.

• PPP3C (PP2B, calcineurin) modulates potassium channel, perhaps by directly controlling the phosphorylation state of potassium channel in collaboration with PKA [4, 5].

• PPP3C interacts with Nuclear factor (NF)-κB-inducing kinase (NIK) and attenuates NIK-dependent gene expression [6].

• In fission yeast, calcineurin interacts with and dephosphorylates kinase Cki3, belonging to CK1-G subfamily, CK1 family, CK1 group. Cki3 autophosphorylate itself in the C terminus, which result in the inhibition of its kinase activity [7].

This phosphatase has clinical significance for schizophrenia and diabetes (see wikipedia).

Besides, PPP3C (PP2B, calcineurin) is an attractive antifungal drug target [8], and its inhibitor (FK506 or cyclosporin A) can be combined with azoles or echinocandins for use against multidrug-resistant Candida species [9].

PPP3CC

PPP3CC is a component of a constitutive intrinsic inflammatory signaling circuit composed of miR-196b, Meis2, PPP3CC, and p65. The signaling circuit drives prostate cancer castration resistance [10] (Entitled A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance).

References

1. Rusnak F and Mertz P. Calcineurin: form and function. Physiol Rev. 2000 Oct;80(4):1483-521. DOI:10.1152/physrev.2000.80.4.1483 |
2. Wang X, Bi Y, Xue L, Liao J, Chen X, Lu Y, Zhang Z, Wang J, Liu H, Yang H, and Liu G. The calcineurin-NFAT axis controls allograft immunity in myeloid-derived suppressor cells through reprogramming T cell differentiation. Mol Cell Biol. 2015 Feb;35(3):598-609. DOI:10.1128/MCB.01251-14 |
3. Wu XS, Zhang Z, Zhao WD, Wang D, Luo F, and Wu LG. Calcineurin is universally involved in vesicle endocytosis at neuronal and nonneuronal secretory cells. Cell Rep. 2014 May 22;7(4):982-8. DOI:10.1016/j.celrep.2014.04.020 |
4. Orie NN, Thomas AM, Perrino BA, Tinker A, and Clapp LH. Ca2+/calcineurin regulation of cloned vascular K ATP channels: crosstalk with the protein kinase A pathway. Br J Pharmacol. 2009 Jun;157(4):554-64. DOI:10.1111/j.1476-5381.2009.00221.x |
5. Brignell JL, Perry MD, Nelson CP, Willets JM, Challiss RA, and Davies NW. Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B. PLoS One. 2015;10(3):e0121285. DOI:10.1371/journal.pone.0121285 |
6. Shinzawa M, Konno H, Qin J, Akiyama N, Miyauchi M, Ohashi H, Miyamoto-Sato E, Yanagawa H, Akiyama T, and Inoue J. Catalytic subunits of the phosphatase calcineurin interact with NF-κB-inducing kinase (NIK) and attenuate NIK-dependent gene expression. Sci Rep. 2015 Jun 1;5:10758. DOI:10.1038/srep10758 |
7. Koyano T, Konishi M, Martin SG, Ohya Y, Hirata D, Toda T, and Kume K. Casein kinase 1γ ensures monopolar growth polarity under incomplete DNA replication downstream of Cds1 and calcineurin in fission yeast. Mol Cell Biol. 2015 May;35(9):1533-42. DOI:10.1128/MCB.01465-14 |
8. Matsoukas MT, Aranguren-Ibáñez Á, Lozano T, Nunes V, Lasarte JJ, Pardo L, and Pérez-Riba M. Identification of small-molecule inhibitors of calcineurin-NFATc signaling that mimic the PxIxIT motif of calcineurin binding partners. Sci Signal. 2015 Jun 23;8(382):ra63. DOI:10.1126/scisignal.2005918 |
9. Yu SJ, Chang YL, and Chen YL. Calcineurin signaling: lessons from Candida species. FEMS Yeast Res. 2015 Jun;15(4):fov016. DOI:10.1093/femsyr/fov016 |