Suppression of survival signalling pathways by the phosphatase PHLPP

Abstract

Summary The recently discovered PH (pleckstrin homology) domain Leucine rich repeat Protein Phosphatase (PHLPP) family is emerging as a central component in suppressing cell survival pathways. Originally discovered in a rational search for a phosphatase that directly dephosphorylates and inactivates Akt, PHLPP is now known to potently suppress cell survival both by inhibiting proliferative pathways and by promoting apoptotic pathways. In the first instance, PHLPP directly dephosphorylates a conserved regulatory site (termed the hydrophobic motif) on Akt, protein kinase C (PKC), and S6 kinase, thereby terminating signalling by these pro-survival kinases. In the second instance, PHLPP dephosphorylates and thus activates the pro-apoptotic kinase Mst1, thereby promoting apoptosis. PHLPP is deleted in a large number of cancers and the genetic deletion of one isozyme in a PTEN (phosphatase and tensin homolog located on chromosome 1) +/− prostate cancer model results in increased tumourigenesis, underscoring the role of PHLPP as a tumour suppressor. This review summarises the targets and cellular actions of PHLPP, with emphasis on its role as a tumour suppressor in the oncogenic PI3K (phosphoinositide 3-kinase)/Akt signalling cascade.

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

“…8 Here we demonstrate that the phosphatase, PHLPP2, is suppressed in AML subtypes, M3, M4 and M5, by miRNAs belonging to the miR-17-92 cluster, oncomir-1. We also show that the phosphatase is significantly upregulated in cells induced toward granulocytic differentiation by ATRA, a drug used for treating AML, through repression of the miR-17-92 cluster.…”

“…Studies on PHLPP family proteins have focused on solid tumors, such as prostate, colorectal and breast cancers, as well as melanomas and non-small cell lung cancers. 8 We show, for the first time, that PHLPP2 is suppressed in more differentiated AML subtypes, M3-M5, identified based on the FAB classification. The FAB system 26 sorts AML on the basis of morphology, cell type and degree of differentiation in contrast to the broader WHO classification, which takes into account factors that impact prognosis.…”

“…As PHLPP2 is deleted or mutated at a high frequency in solid tumors, 8 we checked The Cancer Genome Atlas database 27,28 to determine whether the poor expression of PHLPP2 in AML was also due to gene mutation or deletion. Our analysis revealed that, compared with breast and prostate tumors, the PHLPP2 gene was rarely altered in AML, with no mutations and a deletion rate of o3% (Supplementary Figure S1A).…”

“…Although most studies on PHLPP2 have focused on genetic alterations in solid tumors, 8 PHLPP2 protein expression in small cell lung and colorectal cancers is also restricted through translational suppression 9 and post-transcriptional control by microRNAs (miR or miRNAs), miR-205 and miR-224. 10,11 The PHLPP2 3' untranslated region (3'UTR) harbors complementary binding sites for a subset of miRNAs belonging to the miRNA-17-92 cluster.…”

Antibody crossreactivity between the tumour suppressor PHLPP1 and the proto‐oncogene β‐catenin

“…uring recent years, the PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) has received increasing attention as a tumour suppressor that functions by dephosphorylating and antagonizing the survival-promoting protein kinases AKT, PKC and S6K1 [1]. Previous studies reported that PHLPP1 co-localizes with the tumour suppressor Scribble at cellcell contacts [2], its expression is lost in colorectal cancer tumours [3] and it correlates with expression of PTEN, a tumour suppressor phosphatase that functions as a negative regulator upstream from AKT [2,4].…”