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BNIP-Sα 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 volume 25, pages 2393–2408 (2006)Cite this article

Abstract

Changes in cell morphology are linked to many cellular events including cytokinesis, differentiation, migration and apoptosis. We recently showed that BNIP-Sα 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-Sα 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-Sα could reduce p50RhoGAP binding to RhoA and restore RhoA activation. Furthermore, BNIP-Sα mutants lacking the RhoA-binding motif completely failed to induce cell rounding and apoptosis. Therefore, via unique binding motifs within its BCH domain, BNIP-Sα 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.

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Acknowledgements

Yi Ting Zhou is a Singapore Millennium Foundation Scholar. This work was supported by grants from the Academic Research Fund, The National University of Singapore and the Biomedical Research Council of Singapore. We thank Dr Alan Hall for the generous gifts of the original cDNA for Rho and p50RhoGAP.

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  1. Department of Biological Sciences, Cell Signaling and Developmental Biology Laboratory, The National University of Singapore, Singapore, Republic of Singapore

    Y T Zhou & B C Low

  2. Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Singapore, Republic of Singapore

    G R Guy

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Correspondence to B C Low.

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Zhou, Y., Guy, G. & Low, B. BNIP-Sα 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 25, 2393–2408 (2006). https://doi.org/10.1038/sj.onc.1209274

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