23239

PHLPP1

PHLPP|PLEKHE1|SCOP;PH domain and leucine rich repeat protein phosphatase 1;PHLPP1;PH domain and leucine rich repeat protein phosphatase 1

PH domain leucine-rich repeat-containing protein phosphatase 1|PH domain-containing family E member 1|SCN circadian oscillatory protein|pleckstrin homology domain containing, family E (with leucine rich repeats) member 1|suprachiasmatic nucleus circadian

18q21.33

protein-coding

Count: 2; UniProt,Generif

Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease.CI - Copyright (c) 2011 Elsevier Inc. All rights reserved.

The phosphatidylinositol-3-OH kinase (PI3K)-Akt pathway is activated in cancer by genetic or epigenetic events and efforts are under way to develop targeted therapies. phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is the major brake of the pathway and a common target for inactivation in glioblastoma, one of the most aggressive and therapy-resistant cancers. To achieve potent inhibition of the PI3K-Akt pathway in glioblastoma, we need to understand its mechanism of activation by investigating the interplay between its regulators. We show here that PTEN modulates the PI3K-Akt pathway in glioblastoma within a tumor suppressor network that includes Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) and pleckstrin-homology domain leucine-rich repeat protein phosphatases 1 (PHLPP1). The NHERF1 adaptor, previously characterized by our group as a PTEN ligand and regulator, shows also PTEN-independent Akt-modulating effects that led us to identify the PHLPP1/PHLPP2 Akt phosphatases as NHERF1 ligands. NHERF1 interacts via its PDZ domains with PHLPP1/PHLPP2 and scaffolds heterotrimeric complexes with PTEN. Functionally, PHLPP1 requires NHERF1 for membrane localization and growth-suppressive effects. PHLPP1 loss boosts Akt phosphorylation only in PTEN-negative cells and cooperates with PTEN loss for tumor growth. In a panel of low-grade and high-grade glioma patient samples, we show for the first time a significant disruption of all three members of the PTEN-NHERF1-PHLPP1 tumor suppressor network in high-grade tumors, correlating with Akt activation and patient's abysmal survival. We thus propose a PTEN-NHERF1-PHLPP PI3K-Akt pathway inhibitory network that relies on molecular interactions and can undergo parallel synergistic hits in glioblastoma.

The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.