Difference between revisions of "Phosphatase Subfamily PHLPP"

Revision as of 19:39, 25 August 2015

Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PHLPP (PH domain and leucine rich repeat protein phosphatase)

PHLPP stands for PH domain and leucine rich repeat protein phosphatase.

Evolution

The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. The canonical PH domain as defined by HMM or PSSM profiles from public database are found in most PHLPPs of deuterostomes and lophotrochozoa PHLPPs. However, the ecdysozoa (e.g. Drosophila and Caenorhabditis) PHLPPs have a PH domain quite divergent from the canonical PH domain (see technical note). Since both ecdysozoa and lophotrochozoa are protostomes, the PH domain diverged after ecdysozoa split from protostomes.

Domain

The PHLPP subfamily has a N-terminal PH domain, a various number of leucine rich repeats, phosphatase domain, and a C-terminal PDZ-domain binding motif.

Functions

The PHLPP subfamily dephosphorylates kinases of AGC group at serines in hydrophobic motif.

• PHLPP1 and PHLPP2 dephosphorylates and inactivates kinases of AKT/PKB family at Ser-473 of human AKT1 [1, 2]. PHLPP1 prefers to dephosphorylate AKT2 and PHLPP2 prefers AKT3 [2]. The position Ser-473 located in hydrophobic motif is conserved across bilateria and among the three human members. It is also found in one sponge AKT, but not all three sponge AKTs (see alignment in KinBase).

• The PHLPP subfamily also dephosphorylates PKC at Ser-660 of human PKC-beta [3]. The position Ser-660 located in hydrophobic motif is conserved across metazoa (replaced by Thr in sea urchin) (see KinBase).

• The PHLPP subfamily also dephosphorylates S6 kinase [4].

Loss of PHLPP can increase the level of phosphorylated Survivin, a member of the inhibitor of apoptosis (IAP) family, in gallbladder carcinoma (GBC) cells [5]. But, it is unclear whether PHLPP directly dephosphorylates Survivin.

PHLPP1 and PHLPP2 are implicated in different kinds of cancers, such as colon cancer [6], hypopharyngeal squamous cell carcinomas [7].

References

1. Error fetching PMID 15808505: [Gao05]
2. Error fetching PMID 17386267: [Brognard07]
3. Error fetching PMID 18162466: [Gao08]
4. Error fetching PMID 21986499: [Liu11]
5. Error fetching PMID 25895131: [Qiu15]
6. Error fetching PMID 19079341: [Liu09]
7. Error fetching PMID 25793736: [Zhou15]

Technical notes

PH domain of PHLPP

PHLPPs of deuterostomes (e.g. human) and lophotrochozoa have the PH domain, as detected by HMM or PSSM profiles from Pfam and/or NCBI CDD database. However, we cannot find PH domain in PHLPPs of most ecdysozoa (e.g. Drosophila and Caenorhabditis). When PSI-BLASTing the full sequence of human PHLPP, we found the PH domain in Loa loa PHLPP. We then PSI-BLASTed the PH domain in Loa loa PHLPP and found the PH domains in other nematode PHLPPs. However, we do not find the hits from arthropods. We looked in the domain combination of Drosophila melanogaster PHLPP, which has LRRs and phosphatase domains started from ~100 aa. Because the PH domain is adjacent to LRRs on the N-terminal side, we therefore hypothesized there might a PH domain located somewhere from 1 to 100 aa. We PSI-BLASTed the region and confirmed its sequence similarity to the PH domain of human PHLPP. In sum, the PH domains in arthropods and nematodes are divergent.