Phosphatase Subfamily PPM1E

Phosphatase Classification: Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PPM1E (POXP, FEM-2)

The subfamily is named named after two human PPMs, PPM1E (also known as POXP1, PP2CH, caMKN, CaMKP-N) and PPM1F (also known as POXP2, CAMKP, FEM-2, hFEM-2, CaMKPase). The subfamily has a single copy in most non-vertebrates from Monosiga to ciona, and duplicated when vertebrates emerged. Both PPM1E and PPM1F dephosphorylate kinases CaMK2g [1, 2, 3] and PAK [4], and PPM1E can also dephosphorylate CaMK4 (of different families from CaMK2g).

The subfamily has some potent inhibitors [5].

The subfamily also dephosphorylate 5'-AMP-activated protein kinase (AMPK) [6]. The activation of AMPK is related to the treatment of type 2 diabetes.

Evolution

CAMK2

Functions

Human PPM1E and PPM1F

Human has two members: PPM1E (POPX1, PP2CH, caMKN, CaMKP-N) and PPM1F (POPX2, CAMKP, CaMKPase, FEM-2, hFEM-2).

Human PPM1EHuman PPM1F is widely expressed in different tissues, as shown by Western blotting analysis [7, 8].

PPM1E and PPM1F have different sub-cellular localizations. Human PPM1E is localized to nculear [1]; PPM1F is localized to cytosol [7, 8]. Human PPM1E has two C-terminal nuclear localization signals (NLSs), at 668-702 and 706-742, respectively [2]. The two NLSs can not be computational identified by NLS prediction tools NLS mapper and NLStradamus.

Both PPM1E and PPM1F dephosphorylate and deactivates kinases of CAMK (Ca2+/calmodulin-dependent protein kinase) group as evidenced by extensive studies. CAMK2 is regulated by autophosphorylation at multiple sites, including Thr-286 activates CAMK2. PPM1F dephosphorylate Thr-286 on CAMK2 in fibroblasts [9]. Human PPM1E dephosphorylates CAMK4 and nuclear CAMK2, while PPM1F dephosphorylates CAMK1 and cytosolic CAMK2 [1, 8]. Rat PPM1F extracted from brain also dephosphorylates CAMK2, but not phosphorylase kinase, histones, MBP, α-casein, andd phosphorylase α [10]. In addition, human PPM1F regulates the phosphorylation level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in by dephosphorylating and deactivating CAMKs that are responsible for the phosphorylation of GAPDH.

Both PPM1E and PPM1F can dephosphorylate and inactivate p21 (Cdc42/Rac)-activated kinase (PAK), which is potently activated by autophosphorylation at multiple sites [4]. PPM1E can bind to PAK interacting guanine nucleotide exchange factor PIX [4]. The association between PPM1E/PPM1F with PAX complex may allow PAK to cycle rapidly between active and inactive states [4].

Other substrates and interacting partners:

• Human PPM1F dephoshorylates serine-690 of KIF3A, which is phosphorylated by CAMK2. KIF3A is a motor subunit which forms a heterotrimeric complex with KIF3B, another motor subunit, and KAP3, the non-motor subunit [11].

• Human PPM1E dephosphorylates 5'-AMP-activated protein kinase (AMPK) [6].

• Human PPM1F can dephosphorylate C. elegans fem-3 [8], but fem-3 is only found in Caenorhabditis according to OrthoDB.

• By proteomic approach, it was found that human PPM1F regulates the activity of glycogen synthase kinase-3 (GSK3) [12] and MAPK1/3 [13], therefore regulating cancer cell motility [14]. GSK3 is not the subtratre of PPM1F, and it is unclear whether PPM1F directly dephosphorylate MAPK1/3.

• Human PPM1F interacts with the formin protein mDia1 (DIAPH1) and decreases the ability of mDia1 to activate the transcription of serum response element (SRE) [15].

PPM1E is proposed to be regulated by oxidation/reduction at Cys-359 [16].

C. elegans fem-2

Fem-2 is C. elegans PPM1E, which, together with fem-1 and fem-3, is required by male sexual development in C. elegans [17]. Crystal structure of C. elegans Fem-2 shows two structural domains: N-terminal domain from 13-160 and C-terminal phosphatase domain from 161-436 [18]. Fem-2 associates with fem-1 and fem-3 via its N-terminal domain [18]. However, the N-terminal domain is only found in several nematodes, by BLASTing the region against NR database. Meanwhile, fem-3 is only present in Caenorhabditis by BLASTing the protein sequence of longest isoform against NR database; Fem-1 is found throughout metazoa (see internal data).

Fem-2 exhibits magnesium-dependent casein phosphatase activity in vitro [17].

References

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