Phosphatase Family PPPc

Phosphatase Classification: PPP

PPP can be found in both eukaryotes and prokaryotes. Most organisms from yeast to human, have a similar number of PPP subfamilies, except nematodes. For instance, 14 subfamily were found in C. elegans. PPPs share the highest sequence similarity compared to other phosphatase superfamilies.

(PS: PPP has a large number of regulatory subunits. Perhaps, it is better to study and document their evolution and function by complex.)

PPP1C

The PPP1Cs are catalytic subunits, which function by binding to regulatory subunits. Over 50 different regulatory subunits are known in human and at least 20 in yeast. These different complexes play key roles in various cellular processes from cell cycle progression to glycogen metabolism.

The PPP1Cs have many lineage-specific gene duplications (see phylogenetic tree). In particular, 10 PPP1Cs are found in fruit fly, while 3 in human, 3 in C. elegans, and 4 in yeast.

PPP2C (PP2A)

PPP2C, also known as PP2A, regulates various cellular processes including different signaling pathways, cell cycle progression, DNA replication, gene transcription and protein translation. It is considered to be a principal guardian against tumorigenic transformation. Some viruses target this protein to hijack the host cell.

PPP2C controls the activity of at least 50 different kinases by directly interaction or linked via a anchoring protein. PPP2C not only integrate signals within phoshorylation cascades but also to be the focal point of a distinct post-translational modification, reversible protein methylation.

The catalytic subunit binds to a regulatory subunit PR65 or A subunit, and sometimes a third variable subunit, resulting in a total of about 75 different holoenzyme compositions.

PPP4C (PP4)

PPP4C, catalytic subunit of Protein Phosphatase 4 (PP4) holoenzyme, is closely related to PPP2C, PP2A catalytic subunit. Similar to PP2A, the catalytic subunit can form heterodimers and heterotrimers with regulatory subunits. At least 6 have been found. Both of PP4 and PP2A dephoshorylate the phophorylated histone 2A variant, γ-H2AX, a marker for DNA damage and cell-cycle arrest, but they participate different physiological processes. While PP2A function after DNA damage, PP4 dephosphorylates γ-H2AX during S phase.

PPP6C (PP6)

PPP6C, catalytic subunit of Protein Phosphatase 6 (PP6) holoenzyme, is closely related to PPP2C, PP2A catalytic subunit. Similar to PP2A and PP4, PP6 also dephoshorylates the phophorylated histone 2A variant, γ-H2AX, a marker for DNA damage and cell-cycle arrest. In addition, PP6 also regulates mitotic spindle formation by controlling the T-loop phosphorylation state of the kinase Aurora A bound to its activator TPX2.

PPP3C (PP2B, calcineurin)

PPP3C is a calcium-dependent phosphatase, which binds to regulatory subunit to form heterodimer complex, known as calcineurin (CN) or Protein Phosphatase 2B (PP2B).

It is conserved from yeast to human, and it participates in very various cellular processes, from cell cycle progression to cardiac hypertrophy (see review PMID: 11015619). In particular, it 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. Calcineurin activates a vertebrate-specific transcription factor called NFATc. It is used as a target for several immunosuppressive drugs. This phosphatase has clinical significance for schizophrenia and diabetes.

PPP5C

PPP5C also known as Protein Phospahtase 5 (PP5) is unique among PPP family members in that its catalytic and regulatory domains are contained in the same polypeptide chain. It has a tetratricopeptide repeat (TPR) domain which maintains the phosphatase in an auto-inhibited conformation that is neutralized when the heat shock protein Hsp90, or fatty acids, bind to this region. ε.

The phosphatase interacts with various proteins and participate in multiple signaling pathways. The phosphatase interacts with ATM, ATR, 53BP1, and DNA-depdent protein kianse catalytic subunits (DNA-PKc) following DNA damage. While enchance the activity of ATM and ATR, the phosphatase negatively regulates 53BP1 and DNA-PKc by dephosphorylating them. It regulates Raf-MEK-ERK pathway via inhibiting Raf-1 by dephosphorylating Serine 338. PPP5 is involved in mammalian circadian clock by activating the major clock kinae casein kinase I (CKI) ε. In addition, the elevated levels of this phosphatase may be associated with breast cancer development.

PPP7C (PPEF)

PPEFs contain calmodulin-binding motif IQ and calcium-binding domains EF hand to the N- and C-terminal side of phosphatase domain, respectively, which suggests its involvement in calcium signaling. This would be a reminiscent of another PPP subfamily, PPP3C (calcineurin/PP2B), which are regulated by calmodulin and another EF-hand protein, calcineurin B.

In C. elegans, Drosophila and mammals, PPEF expression was mainly detected in various sensory neurons. The Drosophila PPEF phosphatase, rdgC, is essential for dephosphorylation of rhodopsin. However, mice lacking both PPEF1 and PPEF2 showed no signs of photoreceptor synases. PPEF is present not only in animals but unicellular eukaryotes, indicating its ancient origin and basic functions of eukaryotes. The function and evolution of this phosphatase is reviewed in paper PMID: 19662497.

Nematode-specific PPPs

At least 36 PPPs are only found in C. elegans. Taking account the total number of PPPs in most eukaryotes is less than 20, this expansion is very unusual. However, almost nothing is known about these phosphatases.