A New Member of the Rho Family, Rnd1, Promotes Disassembly of Actin Filament Structures and Loss of Cell Adhesion

Abstract

Members of the Rho GTPase family regulate the organization of the actin cytoskeleton in response to extracellular growth factors. We have identified three proteins that form a distinct branch of the Rho family: Rnd1, expressed mostly in brain and liver; Rnd2, highly expressed in testis; and Rnd3/RhoE, showing a ubiquitous low expression. At the subcellular level, Rnd1 is concentrated at adherens junctions both in confluent fibroblasts and in epithelial cells. Rnd1 has a low affinity for GDP and spontaneously exchanges nucleotide rapidly in a physiological buffer. Furthermore, Rnd1 lacks intrinsic GTPase activity suggesting that in vivo, it might be constitutively in a GTP-bound form. Expression of Rnd1 or Rnd3/RhoE in fibroblasts inhibits the formation of actin stress fibers, membrane ruffles, and integrin-based focal adhesions and induces loss of cell–substrate adhesion leading to cell rounding (hence Rnd for “round”). We suggest that these proteins control rearrangements of the actin cytoskeleton and changes in cell adhesion.

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

“…Overexpression of Rnd3 causes the loss of actin stress fibers in cultured MDCK cells, astrocytes, and Swiss 3T3 fibroblasts 28, 29, 56, 86, 87. In HUVEC, however, Rnd3 expression has been reported to increase actin stress fiber formation, which was attributed to increased transcription and activity of RhoB 36.…”

“…Unlike most GTPases, which cycle between GTP‐ and GDP‐bound states and thus act like molecular switches in signaling pathways, Rnd proteins are deficient in GTPase activity, and are probably regulated in large part at the transcriptional level 26. Rnd3 is the most commonly expressed member of this subfamily and is ubiquitously expressed 27, 28, 29. In addition to transcriptional regulation, Rnd3 is also phosphorylated by ROCK1 and PKCα, promoting its stabilization and translocation between the membrane and cytosolic fractions 30, 31.…”

Coup d’œil sur les petites GTPases Rho

“…Leur incapacité à lier le GDP et à hydrolyser le GTP [25,26] font en sorte qu'elles lient de façon constitutive le GTP et restent insensibles à l'action de GEF ou de GAP. Elles se distinguent également des autres membres de la famille par la présence d'un groupement « F » et non d'un « GG » à leur extrémité carboxy-terminale [25].…”

“…Elles se distinguent également des autres membres de la famille par la présence d'un groupement « F » et non d'un « GG » à leur extrémité carboxy-terminale [25]. Cette absence d'un groupement « GG » leur permet d'échapper à la séquestration cytoplasmique des RhoGDI et explique qu'on retrouve ces protéines principalement localisées aux membranes [25,26]. …”

“…La surexpression de Rnd1 et de Rnd3 dans les fibroblastes amène ces cellules à perdre leurs points d'ancrage et à s'arrondir [26]. Cette observation correspond précisément au phénotype inverse de RhoA.…”