Department of Pharmacology, University of California San Diego, 9500 Gilman Dr., Mail Code 0721, La Jolla, CA 92093, USA
While PHLPP2 and its family member PHLPP1 have similar functions, their specificity for Akt isoforms differs. PHLPP1 preferentially binds and dephosphorylates Akt2 and Akt3, resulting in decreased phosphorylation of a set of Akt targets that includes GSK-3beta, TSC2, and FoxO, as well as HDM2 and GSK3a. PHLPP2, on the other hand, binds and dephosphorylates Akt1 and Akt3, resulting in downregulation of an overlapping yet distinct set of downstream targets: GSK-3beta, TSC2, and FoxO, as well as TSC2 and p27.
PHLPP2 regulates cellular survival and proliferation, partially by regulating Akt. PHLPP2 overexpression increases apoptosis in cancer cell lines under low serum conditions; this effect is partially blocked by overexpressing an Akt mutant that is resistant to dephosphorylation by PHLPP. Conversely, siRNA-mediated knockdown of PHLPP2 decreases basal and etoposide-stimulated apoptosis and increases cellular proliferation.
PHLPP2 may also be involved in cAMP signaling to Akt. PHLPP2 binds adenylyl cyclase type 6 in cardiac myocytes, and treatments that raise cAMP levels decrease Akt HM phosphorylation, possibly through activation of PHLPP.
The L1016S variant of PHLPP2 may be involved in breast cancer. Although most breast cancer cell lines are homozygous for the Leucine allele, some are homozygous for the Serine allele. In addition, the normal breast cell line Hs578Bst is heterozygous (Leu/Ser) at position 1016, while its pair-matched tumor cell line Hs578t has only the Serine allele, suggesting that the gene has undergone loss of heterozygosity in this tumor. Similar results were obtained upon comparing normal and tumor tissues from breast cancer patients who are heterozygous at position 1016. High-grade breast tumors from some of these patients exhibited loss of the Leucine allele, but no tumors exhibited loss of the Serine allele. Further characterization of the L1016S mutant has revealed that its phosphatase activity (as measured by activity toward Akt) and its ability to promote apoptosis are defective. Moreover, siRNA-mediated knockdown of PHLPP2 in Ser/Ser breast cancer cell lines has no effect on Akt phosphorylation or PKCalpha levels, while knocking down PHLPP2 in cell lines with at least one Leucine allele increases Akt phosphorylation and PKCalpha levels. All in all, the data indicate that the version of PHLPP2 with Serine at position 1016 is less functional towards Akt and PKC than the wildtype version, and that loss of the wildtype allele in heterozygous (Leu/Ser) breast cancer patients may be involved in the progression of breast cancer.
NCBI: 23035 MIM: 611066 HGNC: 29149 Ensembl: ENSG00000040199
dbSNP: 23035 ClinVar: 23035 TCGA: ENSG00000040199 COSMIC: PHLPP2
Audrey K ONeill ; Alexandra C Newton
PHLPP2 (PH domain leucine-rich repeat protein phosphatase 2)
Atlas Genet Cytogenet Oncol Haematol. 2009-06-01
Online version: http://atlasgeneticsoncology.org/gene/44546/phlpp2