The Laboratory of Signal Transduction, Molecular Targeting Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Role in actin organization Many studies on the functions of RND3 have been carried out in several cultured cell lines, most of these studies have shown that RND3 could regulate the actin cytoskeleton by inducing loss of stress fibres and cell rounding. Previous studies have shown that RND3 interacts with p190 RhoGAP and might increase the intrinsic GAP activity of p190 RhoGAP for RhoA, thereby reducing RhoA-GTP levels. Recent reports have shown that a KERRA (Lys-Glu-Arg-Arg-Ala) sequence in their N-terminus of RND3 could mediate the lipid raft targeting of p190 RhoGAP correlated with its activation. RND3 could also negatively regulates Syx (a RhoA-GEF) through interacting with Syx Raf1-like ubiquitin-related domain thus act as an antagonists of RhoA signaling. RhoA directly stimulates stress fibres through activation of the serine/threonine kinases ROCK1 and ROCK2. RND3 could interact with the amino-terminal region of ROCK1 comprising the kinase domain, so RND3 competited with other ROCK1 substrates, such as myosin light chain phosphatase, and hence prevent stress fibre formation.
Role in cell cycle regulation Many studies have been indicated that RND3 could inhibit cell proliferation and these data show that RND3 is able to block cell-cycle progression at different phases. Most studies about cell-cycle shown that RND3 could block cell-cycle progression at the G1 phase. The mechanism may be that RND3 could decrease the level of cyclin D1, reduce Rb phosphorylation and transcription of E2F-regulated genes. RND3 blocks the phosphorylation of the translational repressor 4E-BP1 in response to extracellular stimuli and also inhibits the expression and transcriptional activity of the eIF4E target c-Myc. Recent studies show that elevation of RND3 expression markedly increased the expression level of PTEN and p27 and decreased pAkt level, thus inhibit cell-cycle progression. RND3 could also block cell-cycle progression at the G2/M phase. The study in a prostate cancer cell line shows that forced RND3 overexpression inhibits the expression of CDC2 and cyclin B1 which are essential for G2/M transition and induction of G2/M arrest.
Role in cell apoptosis and survival The fuction of RND3 is complex, RND3 can modulate cell survival and apoptosis. RND3 can induce apoptosis in prostate cancer, esophageal squamous cell carcinoma and glioblastoma cell lines. However, in some cancer cell lines, high levels of RND3 can decrease apoptosis and ShRNA mediated RND3 depletion resulted in an increase in apoptosis in response to genotoxic agents or UVB. RND3 could increase survival in osteosarcoma cells through down-regulate the activity of ROCK1 which itself can mediate membrane blebbing and apoptosis in these cells. RND3 may promote the multidrug resistance phenotype of gastric cancer cells by decreasing the expression of pro-apoptotic protein Bax at post-transcriptional level.
Role in development RND3 plays an important role in the normal development, RND3 null mice (RND3 gt/gt) show an abnormal body position with profound motor impairment and impaired performance in most neurobehavioral tests, they are smaller at birth, display growth retardation and early postnatal death. There is a delay of neuromuscular maturation, a reduction in the number of spinal motor neurons, a decrease in the number and the total length of the neurites in the RND3 gt/gt mice. Over-expression of RND3 induces neurite-like formation through inhibition of the RhoA/ROCK-I signalling and also involves in NGF-induced neurite extension.
NCBI: 390 MIM: 602924 HGNC: 671 Ensembl: ENSG00000115963
dbSNP: 390 ClinVar: 390 TCGA: ENSG00000115963 COSMIC: RND3
Xia Hongwei ; Zhang Yucheng ; Bi Feng
RND3 (Rho family GTPase 3)
Atlas Genet Cytogenet Oncol Haematol. 2013-01-01
Online version: http://atlasgeneticsoncology.org/gene/46247/rnd3-(rho-family-gtpase-3)