Suppression of survival signalling pathways by the phosphatase PHLPP - PubMed (original) (raw)

Suppression of survival signalling pathways by the phosphatase PHLPP

Audrey K O'Neill et al. FEBS J. 2013 Jan.

Abstract

The recently discovered pleckstrin homology (PH) 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 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 homologue located on chromosome 1) +/- (or heterozygous) prostate cancer model results in increased tumourigenesis, underscoring the role of PHLPP as a tumour suppressor. This review summarizes the targets and cellular actions of PHLPP, with emphasis on its role as a tumour suppressor in the oncogenic phosphoinositide 3-kinase (PI3K)/Akt signalling cascade.

© 2012 The Authors Journal compilation © 2012 FEBS.

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Figures

Figure 1

Figure 1

Domain structure of the human PHLPP isozymes. All PHLPP family members contain a pleckstrin homology (PH) domain, a series of leucine-rich repeats (LRR), a PP2C phosphatase domain, and a C-terminal PDZ ligand. In addition, PHLPP1β and PHLPP2 contain a putative Ras association (RA) domain near their N-termini.

Figure 2

Figure 2

PHLPP suppresses the PI3K/Akt signalling pathway. Upon activation of growth factor receptors, PI3K is recruited by insulin receptor substrate-1 (IRS-1) and other proteins to the receptors, where it is activated by phosphorylation, resulting in production of the second messenger PIP3 at the plasma membrane. Upon this stimulus, Akt translocates to the plasma membrane, where it is activated by phosphorylation at the activation loop (T308) and hydrophobic motif (S473). Fully phosphorylated, active Akt phosphorylates a range of downstream substrates, including TSC2, which indirectly regulates mTOR, and GSK3β. Several phosphatases (bright red) act to restrain PI3K/Akt pathway activation, including the lipid phosphatase PTEN, which dephosphorylates PIP3, removing the upstream signal for Akt activation, and the protein phosphatases PP2A and PHLPP, which dephosphorylate Akt at T308 (the activation loop) and S473 (the hydrophobic motif), respectively. Note that PHLPP also dephosphorylates S6K1 at its hydrophobic motif, repressing protein synthesis and activating the S6K/IRS-1 feedback loop. PHLPP expression is tightly regulated downstream of Akt, resulting in negative feedback via two mechanisms. First, mTORC1 activation increases PHLPP1 and PHLPP2 protein translation via activation of S6K and inhibition of 4EBP1; second, GSK3β-mediated phosphorylation of PHLPP1 results in increased PHLPP degradation mediated by the E3 ligase β-TrCP. Thus, repression of GSK3β by Akt prevents PHLPP degradation and increases PHLPP protein levels.

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