BNIP-Salpha induces cell rounding and apoptosis by displacing p50RhoGAP and facilitating RhoA activation via its unique motifs in the BNIP-2 and Cdc42GAP homology domain

Oncogene. 2006 Apr 13;25(16):2393-408. doi: 10.1038/sj.onc.1209274.


Changes in cell morphology are linked to many cellular events including cytokinesis, differentiation, migration and apoptosis. We recently showed that BNIP-Salpha induced cell rounding that leads to apoptosis via its BNIP-2 and Cdc42GAP Homology (BCH) domain, but the underlying mechanism has not been determined. Here, we have identified a unique region (amino acid 133-177) of the BNIP-Salpha BCH domain that targets RhoA, but not Cdc42 or Rac1 and only the dominant-negative form of RhoA could prevent the resultant cell rounding and apoptotic effect. The RhoA-binding region consists of two parts; one region (residues 133-147) that shows some homology to part of the RhoA switch I region and an adjacent sequence (residues 148-177) that resembles the REM class I RhoA-binding motif. The sequence 133-147 is also necessary for its heterophilic interaction with the BCH domain of the Rho GTPase-activating protein, p50RhoGAP/Cdc42GAP. These overlapping motifs allow tripartite competition such that overexpression of BNIP-Salpha could reduce p50RhoGAP binding to RhoA and restore RhoA activation. Furthermore, BNIP-Salpha mutants lacking the RhoA-binding motif completely failed to induce cell rounding and apoptosis. Therefore, via unique binding motifs within its BCH domain, BNIP-Salpha could interact and activate RhoA while preventing its inhibition by p50RhoGAP. This concerted mechanism could allow effective propagation of the RhoA pathway for cell rounding and apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / physiology*
  • Amino Acid Motifs
  • Apoptosis*
  • Binding Sites
  • Cell Line, Tumor
  • Cytoskeleton / chemistry
  • GTPase-Activating Proteins / physiology*
  • Humans
  • Protein Structure, Tertiary
  • cdc42 GTP-Binding Protein / chemistry*
  • rhoA GTP-Binding Protein / chemistry
  • rhoA GTP-Binding Protein / metabolism*


  • Adaptor Proteins, Signal Transducing
  • BNIPL protein, human
  • GTPase-Activating Proteins
  • rho GTPase-activating protein
  • cdc42 GTP-Binding Protein
  • rhoA GTP-Binding Protein