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 and PHLPP2, which most likely originated from vertebrate whole genome duplication. A likely homolog exists in fungi, where it is fused to adenylate cyclase (CYR1 in Saccharomyces cerevisiae).

Domain

The PHLPP subfamily has a N-terminal putative ras-association (RA) domain, 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

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 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.