Rit Contributes to Nerve Growth Factor-Induced Neuronal Differentiation via Activation of B-Raf-Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Cascades

Shi, Guangpu; Andres, Douglas A.

doi:10.1128/mcb.25.2.830-846.2005

Cited by 65 publications

(171 citation statements)

References 80 publications

(150 reference statements)

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“…S6C). Notably, expression of RIT1 S35N , a presumptive dominant negative mutant analogous to RAS N17 (27), did not impair basal or EGF-induced ERK activation. These data suggest that RIT1 does not play a major role in normal RAS-ERK pathway activation, at least in Flp-In T-REx293 cells; i.e., the NS-associated mutants act as neomorphs.…”

Section: Significancementioning

confidence: 99%

“…RIT1 belongs to the RAS superfamily of small GTPases, and is >50% identical to RAS. Previous studies showed that an activated mutant of RIT1 (p.Q79L) can increase p38 MAPK and/or ERK activation in a cell-specific manner (27). The NS-associated mutations localize to the G2 domain (A57), G3 domain (A77), and switch II region (F82 and G95), which are conserved across vertebrates ( Fig.…”

Section: Significancementioning

confidence: 99%

“…To assess their effects on signaling, we recombined Flagged tagged (FL-) versions of each variant, as well as known activated (Q79L) and impaired (S35N) RIT1 mutants (27), into Flp-In T-REx 293 cells. This cell system enables tetracycline-inducible expression of constructs integrated into the same locus.…”

Section: Significancementioning

confidence: 99%

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Next-generation sequencing identifies rare variants associated with Noonan syndrome

Chen

Yin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

157

148

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Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed nextgeneration sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gainof-function alleles in Ras-like without CAAX 1 (RIT1) and mitogenactivated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that nextgeneration sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.human genetics | developmental diseases | whole exome sequencing | PTPN11 | RAS

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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Next-generation sequencing identifies rare variants associated with Noonan syndrome

Chen

Yin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

157

148

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“…Ras GTPases respond to external signals by exchanging GTP for bound GDP, which enables interaction with downstream effector proteins, thereby linking extracellular signals to specific intracellular signaling cascades that mediate diverse cellular functions, including cell differentiation (Reuther and Der, 2000). We recently demonstrated that nerve growth factor (NGF) activates Rit and that Rit-GTP contributes to NGF-induced neurite growth in pheochromocytoma and SH-SY5Y cells (Spencer et al, 2002b;Hynds et al, 2003;Shi and Andres, 2005), suggesting that Rit signaling may be involved in controlling neuronal morphogenesis. The finding that Rit associates with the Par3-Par6 complex , which is involved in axon-dendrite specification in cultured hippocampal neurons (Shi et al, 2003), also supports a role for Rit in neuronal morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

The Novel GTPase Rit Differentially Regulates Axonal and Dendritic Growth

Lein¹,

Guo²,

Shi³

et al. 2007

J. Neurosci.

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The Rit GTPase is widely expressed in developing and adult nervous systems, and our previous data with pheochromocytoma cells implicate Rit signaling in NGF-induced neurite outgrowth. In this study, we investigated a role for Rit in neuronal morphogenesis. Expression of a dominant-negative (dn) Rit mutant in hippocampal neurons inhibited axonal growth but potentiated dendritic growth. Conversely, a constitutively active (ca) Rit mutant promoted axonal growth but inhibited dendritic growth. Dendritogenesis is regulated differently in sympathetic neurons versus hippocampal neurons in that sympathetic neurons require NGF and bone morphogenetic proteins (BMPs) to trigger dendritic growth. Despite these differences, dnRit potentiated and caRit blocked BMP7-induced dendritic growth in sympathetic neurons. Biochemical studies indicated that BMP7 treatments that caused dendritic growth also decreased Rit GTP loading. Additional studies demonstrate that caRit increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and pharmacological inhibition of MEK1 (mitogen-activated protein kinase/ERK 1) blocked the axon-promoting and dendrite-inhibiting effects of caRit. These observations suggest that Rit is a convergence point for multiple signaling pathways and it functions to promote axonal growth but inhibit dendritic growth via activation of ERK1/2. Modulation of the activational status of Rit may therefore represent a generalized mechanism across divergent neuronal cell types for regulating axonal versus dendritic growth modes.

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“…Cells were transfected 72 h using Jetprime transfection reagent after the initial plating, which is necessary for HNPCs to regain contact. All DNA constructs used in this study have been described previously (27,28,54,55). Jetprime transfection reagent has been shown previously to mediate efficient transfection of murine neuronal stem cells (53).…”

Section: Methodsmentioning

confidence: 99%

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

Mir

Cai

Andres

2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAdult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt-dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation.

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Rit Contributes to Nerve Growth Factor-Induced Neuronal Differentiation via Activation of B-Raf-Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Cascades

Cited by 65 publications

References 80 publications

Next-generation sequencing identifies rare variants associated with Noonan syndrome

Next-generation sequencing identifies rare variants associated with Noonan syndrome

The Novel GTPase Rit Differentially Regulates Axonal and Dendritic Growth

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

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