CD44 acts through RhoA to regulate YAP signaling

Cell Signal. 2014 Nov;26(11):2504-13. doi: 10.1016/j.cellsig.2014.07.031. Epub 2014 Aug 4.

Abstract

The Hippo pathway plays an important role in both physical and pathogenesis processes. As crucial downstream effectors of Hippo pathway, YAP is inhibited by Lats1/2 through phosphorylation. However, upstream signals that regulate the Hippo pathway have been still poorly understood. Here, we found that knockdown of CD44 reduced YAP expression and nuclear localization, but nearly had no effect on its upstream effectors, Mst1 and Lats1. Downregulated CD44 expression also significantly decreased the expression of YAP downstream effectors CTGF, Cyr61 and EDN1 at mRNA level. Our next study showed that knockdown of CD44 inhibited RhoA expression, which was consistent with RhoA knockdown mediated YAP downregulation. Furthermore, we demonstrated that over expression of the constitutively active RhoA (RhoA-V14) could block the YAP expression decrease mediated by CD44 knockdown. Moreover, downregulation of CD44 significantly promoted cell apoptosis and inhibited cell proliferation, cell cycle progression and migration, which were consistent with the effects of RNAi-mediated YAP knockdown in both A549 and HepG2 cells. Overall, data are presented showing that CD44 could act through RhoA signaling to regulate YAP expression and this study also provide new insights into the regulatory mechanisms of the Hippo-YAP pathway.

Keywords: CD44; Hippo; RhoA; YAP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / physiology
  • Cell Cycle Proteins
  • Cell Movement / physiology
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Cysteine-Rich Protein 61 / genetics
  • Cysteine-Rich Protein 61 / metabolism
  • Gene Expression Regulation / physiology*
  • Hep G2 Cells
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / physiology*
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • CCN1 protein, human
  • CCN2 protein, human
  • CD44 protein, human
  • Cell Cycle Proteins
  • Cysteine-Rich Protein 61
  • Hyaluronan Receptors
  • Nuclear Proteins
  • Transcription Factors
  • YY1AP1 protein, human
  • RHOA protein, human
  • Connective Tissue Growth Factor
  • LATS1 protein, human
  • STK4 protein, human
  • Protein-Serine-Threonine Kinases
  • rhoA GTP-Binding Protein