Phosphatase Subfamily PHLPP

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

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, followed by several 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. Gao T, Furnari F, and Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005 Apr 1;18(1):13-24. DOI:10.1016/j.molcel.2005.03.008 |
2. Brognard J, Sierecki E, Gao T, and Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007 Mar 23;25(6):917-31. DOI:10.1016/j.molcel.2007.02.017 |
3. Gao T, Brognard J, and Newton AC. The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem. 2008 Mar 7;283(10):6300-11. DOI:10.1074/jbc.M707319200 |
4. Liu J, Stevens PD, Li X, Schmidt MD, and Gao T. PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth. Mol Cell Biol. 2011 Dec;31(24):4917-27. DOI:10.1128/MCB.05799-11 |
5. Qiu Y, Li X, Yi B, Zheng J, Peng Z, Zhang Z, Wu M, Shen F, and Su C. Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting Survivin phosphorylation and nuclear export in gallbladder cancer. Oncotarget. 2015 Aug 7;6(22):19148-62. DOI:10.18632/oncotarget.3721 |
6. Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM, and Gao T. Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis. Oncogene. 2009 Feb 19;28(7):994-1004. DOI:10.1038/onc.2008.450 |
7. Zhou J, Yu X, Wang J, Li T, Jin T, Lei D, and Pan X. Aberrant expression of PHLPP1 and PHLPP2 correlates with poor prognosis in patients with hypopharyngeal squamous cell carcinoma. PLoS One. 2015;10(3):e0119405. DOI:10.1371/journal.pone.0119405 |

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.