RanBPM is essential for mouse spermatogenesis and oogenesis

Puverel, Sandrine; Barrick, Colleen; Dolci, Susanna; Coppola, Vincenzo; Tessarollo, Lino

doi:10.1242/dev.062505

Cited by 45 publications

(73 citation statements)

References 57 publications

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“…2A, indicated by an arrow). Another recent study which produced RanBP9 null mice using the same strategy as ours also reported that most Ran−/− pups died immediately after birth, though some mice survived to adult hood albeit with reduced body weight [22]. But in our hand almost all pups died by postnatal day 2.…”

Section: Resultssupporting

confidence: 63%

RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice

et al. 2013

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RanBP9 is known to act as a scaffolding protein bringing together a variety of cell surface receptors and intracellular targets thereby regulating functions as diverse as neurite and axonal outgrowth, cell morphology, cell proliferation, myelination, gonad development, myofibrillogenesis and migration of neuronal precursors. Though RanBP9 is ubiquitously expressed in all tissues, brain is one of the organs with the highest expression levels of RanBP9. In the neurons, RanBP9 is localized mostly in the cytoplasm but also in the neurites and dendritic processes. We recently demonstrated that RanBP9 plays pathogenic role in Alzheimer’s disease. To understand the role of RanBP9 in the brain, here we generated RanBP9 null mice by gene-trap based strategy. Most of Ran−/− mice die neonatally due to defects in the brain growth and development. The major defects include smaller cortical plate (CP), robustly enlarged lateral ventricles (LV) and reduced volume of hippocampus (HI). The lethal phenotype is due to a suckling defect as evidenced by lack of milk in the stomachs even several hours after parturition. The complex somatosensory system which is required for a behavior such as suckling appears to be compromised in Ran−/− mice due to under developed CP. Most importantly, RanBP9 phenotype is similar to ERK1/2 double knockout and the neural cell adhesion receptor, L1CAM knockout mice. Both ERK1 and L1CAM interact with RanBP9. Thus, RanBP9 appears to control brain growth and development through signaling mechanisms involving ERK1 and L1CAM receptor.

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Section: Resultssupporting

confidence: 63%

RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice

et al. 2013

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“…The protein components of this complex include muskelin, RanBP9/RanBPM, TWA1, MAEA, Rmnd5a and Armc8 [1]. Molecular cell biological and gene knockout or knockdown studies of individual proteins indicate a wide repertoire of activities that include roles of muskelin in cell morphology, transcriptional regulation and synaptic processes [3–5]; of RanBP9 in ERK signalling, neurodegeneration and spermatogenesis [6–8]; and of Armc8 in modulating stability of hepatocyte growth factor-regulated tyrosine kinase substrate or β-catenin [9,10]. Xenopus tropicalis Rmnd5 has been demonstrated to have E3 ubiquitin ligase activity in vitro and to be important for embryonic development of the Xenopus mesencephalon, prosencephalon and eye in vivo [11].…”

Section: Introductionmentioning

confidence: 99%

Studies of recombinant TWA1 reveal constitutive dimerization

et al. 2017

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The mammalian muskelin/RanBP9/C-terminal to LisH (CTLH) complex and the Saccharomyces cerevisiae glucose-induced degradation (GID) complex are large, multi-protein complexes that each contain a RING E3 ubiquitin ligase. The yeast GID complex acts to degrade a key enzyme of gluconeogenesis, fructose 1,6-bisphosphatase, under conditions of abundant fermentable carbon sources. However, the assembly and functions of the mammalian complex remain poorly understood. A striking feature of these complexes is the presence of multiple proteins that contain contiguous lissencephaly-1 homology (LisH), CTLH and C-terminal CT11-RanBP9 (CRA) domains. TWA1/Gid8, the smallest constituent protein of these complexes, consists only of LisH, CTLH and CRA domains and is highly conserved in eukaryotes. Towards better knowledge of the role of TWA1 in these multi-protein complexes, we established a method for bacterial expression and purification of mouse TWA1 that yields tag-free, recombinant TWA1 in quantities suitable for biophysical and biochemical studies. CD spectroscopy of recombinant TWA1 indicated a predominantly α-helical protein. Gel filtration chromatography, size-exclusion chromatography (SEC) with multi-angle light scattering (SEC-MALS) and native PAGE demonstrated a propensity of untagged TWA1 to form stable dimers and, to a lesser extent, higher order oligomers. TWA1 has a single cysteine residue, Cys139, yet the dimeric form was preserved when TWA1 was purified in the presence of the reducing agent tris(2-carboxyethyl)phosphine (TCEP). These findings have implications for understanding the molecular role of TWA1 in the yeast GID complex and related multi-protein E3 ubiquitin ligases identified in other eukaryotes.

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“…Analyses of RanBPM-deficient mice have recently shown a role for RanBPM in gametogenesis in both genders [16]. Several reports have also suggested that RanBPM functions as a regulator of apoptotic pathways through its interaction with several apoptotic regulators such as cyclin-dependent kinase CDK11p46, the p75 neurotrophin receptor (p75NTR), p73, and homeodomain interacting protein kinase-2 (HIPK-2) [17], [18], [19], [20].…”

Section: Introductionmentioning

confidence: 99%

RanBPM Is an Inhibitor of ERK Signaling

Atabakhsh¹,

Schild-Poulter

2012

PLoS ONE

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Ran-binding protein M (RanBPM) is a nucleocytoplasmic protein of yet unknown function. We have previously shown that RanBPM inhibits expression of the anti-apoptotic factor Bcl-2 and promotes apoptosis induced by DNA damage. Here we show that the effects of RanBPM on Bcl-2 expression occur through a regulation of the ERK signaling pathway. Transient and stable down-regulation of RanBPM stimulated ERK phosphorylation, leading to Bcl-2 up-regulation, while re-expression of RanBPM reversed these effects. RanBPM was found to inhibit MEK and ERK activation induced by ectopic expression of active RasV12. Activation of ERK by active c-Raf was also prevented by RanBPM. Expression of RanBPM correlated with a marked decrease in the protein levels of ectopically expressed active c-Raf and also affected the expression of endogenous c-Raf. RanBPM formed a complex with both active c-Raf, consisting of the C-terminal kinase domain, and endogenous c-Raf in mammalian cells. In addition, RanBPM was found to decrease the binding of Hsp90 to c-Raf. Finally, we show that loss of RanBPM expression confers increased cell proliferation and cell migration properties to HEK293 cells. Altogether, these findings establish RanBPM as a novel inhibitor of the ERK pathway through an interaction with the c-Raf complex and a regulation of c-Raf stability, and provide evidence that RanBPM loss of expression results in constitutive activation of the ERK pathway and promotes cellular events leading to cellular transformation and tumorigenesis.

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RanBPM is essential for mouse spermatogenesis and oogenesis

Cited by 45 publications

References 57 publications

RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice

RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice

Studies of recombinant TWA1 reveal constitutive dimerization

RanBPM Is an Inhibitor of ERK Signaling

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