PHLPP1 regulates contact inhibition by dephosphorylating Mst1 at the inhibitory site

Biochem Biophys Res Commun. 2014 Jan 24;443(4):1263-9. doi: 10.1016/j.bbrc.2013.12.129. Epub 2014 Jan 3.

Abstract

Contact inhibition has been largely elusive despite that a loss of contact inhibition is a critical event for cancer development and progression. Here, we report that PHLPP1 is a binding protein for Mst1 and it modulates the Hippo pathway by dephosphorylating Mst1 at the inhibitory Thr(387) of Mst1. Yap1 was localized predominantly in the nucleus but marginally in the cytoplasm in HeLa cells under sparse conditions, whereas the functional protein was more directed to sequestration in the cytoplasm under dense environments. Furthermore, loss of PHLPP1 resulted in a failure of the apoptotic control. It is interesting that down-regulated expression of PHLPP1 appears to mimic the loss of contact inhibition, a hallmark of cancer.

Keywords: Contact inhibition; Hippo pathway; Mst1; PHLPP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis
  • Binding Sites
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Contact Inhibition / physiology*
  • Cytoplasm / metabolism
  • HeLa Cells
  • Hippo Signaling Pathway
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Transcription Factors
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • STK4 protein, human
  • Protein Serine-Threonine Kinases
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases