Roles of BNIPXL in regulating cell growth and morphology

Abstract

We first described the BNIP-2 and Cdc42GAP Homology (BCH) domain of BNIP-2 as a novel regulator of cell morphogenesis by targeting specific Cdc42, a member of Rho GTPases. To elucidate the functional significance of such domain, we identified BNIPXL (for BNIP-2 Extra-Long) that encompasses most of the BNIP-2 sequence at the C-terminus. It exists as two alternatively spliced isoforms and could form homophilic and heterophilic complexes with itself or others via its BCH domain. Unlike BNIP-2, the BCH domain of BNIPXL also binds RhoA but not Cdc42 or Rac1 and is sufficient to elicit filopodia and membrane protrusions. Loss of RhoA binding to its BCH domain, presence of dominant negative RhoA or presence of PAK-CRIB domain that sequesters active Cdc42, could abolish these effects. These results indicate that BNIPXL inactivates RhoA but activates Cdc42/Rac pathways, and highlight the plasticity of the BCH domain in conferring distinct cell morphogenesis through unique GTPase-binding motifs.