Phosphatase Subfamily PHLPP

Phosphatase Classification: Fold PPM: Superfamily PPM: Family PPM: Subfamily PHLPP

PHLPP (PH domain leucine-rich repeat protein phosphatases) phosphatases regulate Akt, PKC and other AGC kinases through dephosphorylation of their hydrophobic motifs

Evolution

The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. A likely homolog exists in fungi, where it is fused to adenylate cyclase. In Saccharomyces CYR1, it is the only adenylate cylcase gene in the genome.

Domain

The PHLPP subfamily has a N-terminal putative ras-binding domain (RBD), followed by a PH domain, several leucine rich repeats, a phosphatase domain, and (in vertebates) a C-terminal PDZ-domain binding motif. Ecdysozoa (e.g. Drosophila and Caenorhabditis) have a divergent PH domain that scores poorly on HMM or PSSM profiles from public databases (see technical note), and Muscomorpha, including Drosophila, have lost the PH and RBD, while within nematodes, Caenorhabditids have also lost the RBD.

Functions

PHLPP dephosphorylates AGC group kinases at serines in their hydrophobic motif, in particular members of the Akt and PKC families.

• PHLPP1 and PHLPP2 dephosphorylate and inactivate Akt kinases at Ser-473 of human AKT1 [1, 2]. PHLPP1 prefers to dephosphorylate AKT2 and PHLPP2 prefers AKT3 [2]. The position Ser-473 located in the hydrophobic motif is conserved across bilateria and among the three human members. It is also found in one sponge AKT, but absent from other sponge AKTs (see alignment in KinBase).

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

• PHLPP 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, including colon cancer [6] and hypopharyngeal squamous cell carcinomas [7].

References

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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 found weak hits toward LRR region but not PH region of human PHLPP2. Thus, our best guess is that PH domain is absent from arthropod PHLPP.