Phosphatase Subfamily PPM1H

Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PPM1H

Evolution

The PPM1H subfamily are found throughout animals from sponge to human. In invertebrates, it usually has a single copy per genome. Human has three copies, arose by two independent duplication events. The genes PPM1H and PPM1J emerged by duplication in early vertebrates or chordates; the gene PPM1M emerged later in sarcopterygii (lobe-finned fish + terrestrial vertebrates). Neither of the duplication events were whole-genome duplication, as evidenced by no obvious double-conserved synteny were detected.

Domain

The PPM1H subfamily has a single structural domain, phosphatase domain. No obvious target peptide has been found so far, so PPM1Hs probably functions mainly in cytoplasm.

Functions

Tissue-specific expression and subcellular localization

The three human members have distinct expression pattern across tissues, according the RNA-seq data from GTEx and studies on individual phosphatases by northern blot analysis or similar assays. They are expressed in a broad types of tissues, but most abundantly in different tissues:

• PPM1H in brain, localized in neurites, growth cones and nucleus of neurons [1].
• PPM1J in testis [2].
• PPM1M in white cell and spleen, localized mainly in cell nuclei [3].

In addition, PPM1H is over-expressed in colon cancer cell lines, where PPM1H is localized in cytoplasm [4].

Substrates and interacting parterns

PPM1H directly interacted with Smad1/5/8 through its Smad-binding domain, and dephosphorylates phospho-Smad1/5/8 (P-Smad1/5/8) in the cytoplasm [5]. The Smad1/2/8 are critical players in bone morphogenetic protein (BMP) signaling, which are also phosphorylated by PPM1A [6].

PPM1H was found to dephosphorylate the tumor suppressor p27 at Thr-187, in a search for trastuzumab (Herceptin) resistance mechanism(s) by RNAi screening [7]. The dephosphorylation remove a signal for proteasomal degradation from p27.

PPM1H also associatesd with and probably dephosphorylates CSE1L, a proliferation and apoptosis-related protein [4].

PPM1J associated with ubiquitin conjugating enzyme 9 (UBC9) [2].

PPM1M dephosphorylated IKKβ in vitro [8].

References

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