View source for Phosphatase Subfamily PPM1L

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PPM1L|Subfamily PPM1L]] (PP2Cε, PP2Ce)

=== Evolution ===
PPM1L is found in most chordate and arthropod genomes, indicating that it emerged in [http://en.wikipedia.org/wiki/Bilateria bilateria] and was lost in nematodes. PPM1L is most closely related to [[Phosphatase_Subfamily_PPM1K|PPM1K]], a mitochondrial phosphatase.

=== Domain ===
PPM1L has an N-terminal transmembrane (TM) region, followed by PPM phosphatase domain. The TM (residues (26-45) of Human PPM1L has been experimentally validated, and the phosphatase domain shown to be on the cytoplasmic side of the membrane <cite>Saito08</cite>; the TMs of sea urchin and Drosophila PPM1Ls are predicted by sequence analysis [[http://www.cbs.dtu.dk/services/TMHMM/ TMHMM]].

=== Functions ===
Human PPM1L is widely expressed in different tissues. Although it is most abundant in heart, placenta, lung, liver, kidney and pancreas as shown by RT-PCR <cite>Jin04</cite>, RNA-seq data from [[http://www.gtexportal.org/home/gene/PPM1L GTEx]] showed different tissue distribution.  

Human PPM1L has the following characterized substrates:
* TAK1. Human PPM1L associated with, dephosphorylated and inactivated TAK1 in vitro <cite>Li03</cite>. TAK1 can be also dephosphorylated by another PPM, [[Phosphatase_Subfamily_PPM1A#PPM1B_.28PP2C.CE.B2.29|PPM1B]], and associates with another PPM, the pseudophosphatase [[Phosphatase_Subfamily_TAB1|TAB1]]. [http://kinase.com/wiki/index.php/Kinase_Subfamily_TAK1 TAK1] emerged in holozoa.
* ASK1 (at Thr-845). Human PPM1L dephosphorylated ASK1 in vitro and associated with ASK1 in mouse brain extracts <cite>Saito07</cite>. ASK1 is also dephosphorylated by PP5, a member of the [[Phosphatase_Subfamily_PPP5C|PPP5C] subfamily of PPP phosphatases. The difference between PPM1L and PP5 is upon H2O2 exposure, PPM1L dissociated with ASK1, while PP5 associated with ASK1 <cite>Saito07</cite>. ASK1 also emerged in holozoa. TAK1 and ASK1 are both [http://kinase.com/wiki/index.php/Kinase_Family_STE11 STE11/MAP3K] kinases.
* [http://en.wikipedia.org/wiki/COL4A3BP Ceramide transport protein CERT] (official symbol COL4A3BP) <cite>Saito08</cite>. Human PPM1L dephosphorylates CERT in a manner depending on [http://en.wikipedia.org/wiki/VAPA vesicle-associated membrane protein-associated protein A (VAPA)], which is an ER resident integral membrane protein involved in recruiting lipid-binding proteins such as CERT to ER membrane. The dephosphorylation resulted in the redistribution of CERT from cytoplasm to Golgi apparatus. PPM1L also interacts with VAPA in vivo. Given that PPM1L is localized in ER, CERT is probably its physiological substrate. A model of PPM1L, VAPA, CERT and the fourth protein ACBD3 is proposed in <cite>Shinoda12</cite>. In comparison with PPM1L, CERT and VAPA emerged much earlier: CERT is found in almost all holozoa and VAPA in almost all eukaryotes.

PPM1L is down-regulated in APC mutation-negative familial colorectal cancer patients <cite>Thean10</cite>.

=== References ===
<biblio>
#Jin04 pmid=15560375
#Li03 pmid=12556533
#Saito07 pmid=17456047
#Saito08 pmid=18165232
#Shinoda12 pmid=22796112
#Thean10 pmid=19847890
</biblio>