M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation

Watanabe-Takano, Haruko; Takano, Kazunori; Keduka, E.; Endo, Takeshi

doi:10.1016/j.yexcr.2009.09.028

Cited by 32 publications

(23 citation statements)

References 65 publications

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“…Western blotting was carried out as described previously (56). For the analysis using antibodies for DA-Raf and phospho-proteins, antibodies were diluted with Can Get signal immunoreaction enhancer solution (TOYOBO) and applied to membranes for overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

Watanabe-Takano

Takano

Sakamoto

et al. 2014

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

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Alveolar formation is coupled to the spatiotemporally regulated differentiation of alveolar myofibroblasts (AMYFs), which contribute to the morphological changes of interalveolar walls. Although the Ras-ERK signaling pathway is one of the key regulators for alveolar formation in developing lungs, the intrinsic molecular and cellular mechanisms underlying its role remain largely unknown. By analyzing the Ras-ERK signaling pathway during postnatal development of lungs, we have identified a critical role of DA-Raf1 (DA-Raf)-a dominant-negative antagonist for the Ras-ERK signaling pathway-in alveolar formation. DA-Raf-deficient mice displayed alveolar dysgenesis as a result of the blockade of AMYF differentiation. DA-Raf is predominantly expressed in type 2 alveolar epithelial cells (AEC2s) in developing lungs, and DA-Rafdependent MEK1/2 inhibition in AEC2s suppresses expression of tissue inhibitor of matalloprotienase 4 (TIMP4), which prevents a subsequent proteolytic cascade matrix metalloproteinase (MMP)14-MMP2. Furthermore, MMP14-MMP2 proteolytic cascade regulates AMYF differentiation and alveolar formation. Therefore, DA-Raf-dependent inhibition of the Ras-ERK signaling pathway in AEC2s is required for alveolar formation via triggering MMP2 activation followed by AMYF differentiation. These findings reveal a pivotal role of the Ras-ERK signaling pathway in the dynamic regulation of alveolar development.

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Section: Methodsmentioning

confidence: 99%

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

Watanabe-Takano

Takano

Sakamoto

et al. 2014

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

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“…Our results identify a novel role for MRAS, which was thus far known for its involvement in differentiation processes (Kimmelman et al, 2002;Sun et al, 2006;Watanabe-Takano et al, 2010). We showed that downregulation of Mras expression in mESCs deconstructs the stemness program by decreasing the expression of Oct4 and of some Pluri genes, such as Ceacam1 and Esrrb, and diminishes the self-renewal capacity of the cells.…”

Section: Research Articlementioning

confidence: 63%

“…MRAS overexpression or its activation was previously shown to induce differentiation in various cell models (Kimmelman et al, 2002;Sun et al, 2006;Watanabe-Takano et al, 2010). We tested the effect of overexpression of MRAS in mESCs grown with or without LIF.…”

Section: Overexpression Of Mras Leads To Different Cellular Phenotypesmentioning

confidence: 99%

“…Mras expression is under the control of the KLF5 transcription factor (Parisi and Russo, 2011;Parisi et al, 2010), with elevated transcripts in specific brain areas, heart and the developing bones. The protein is concentrated on plasma membrane-associated structures (Kimmelman et al, 1997;Kimmelman et al, 2002;Matsumoto et al, 1997;Watanabe-Takano et al, 2010). MRAS expression and its GTPase activity are stimulated by nerve growth factor (NGF) in pheochromocytoma PC12 cells, in which it triggers ERK-dependent neuronal differentiation (Kimmelman et al, 2002;Sun et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…MRAS expression and its GTPase activity are stimulated by nerve growth factor (NGF) in pheochromocytoma PC12 cells, in which it triggers ERK-dependent neuronal differentiation (Kimmelman et al, 2002;Sun et al, 2006). MRAS expression is also stimulated by the BMP2 signalling pathway in myoblast C2C12 cells, in which it induces osteoblast differentiation under the control of the p38 and JNK kinases (Watanabe-Takano et al, 2010). Activated forms of MRAS, such as the MRAS-G22V mutant which is constitutively in the GTP-bound form, mimic inducers (NGF or BMP2) and trigger neuronal or osteoblast differentiation in PC12 or C2C12 models, respectively (Kimmelman et al, 2002;Sun et al, 2006;WatanabeTakano et al, 2010), induce formation of peripheral microspikes in fibroblasts and participate in the reorganisation of the actin cytoskeleton (Matsumoto et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate

et al. 2013

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SUMMARYPluripotent mouse embryonic stem cells (mESCs), maintained in the presence of the leukemia inhibitory factor (LIF) cytokine, provide a powerful model with which to study pluripotency and differentiation programs. Extensive microarray studies on cultured cells have led to the identification of three LIF signatures. Here we focus on muscle ras oncogene homolog (MRAS), which is a small GTPase of the Ras family encoded within the Pluri gene cluster. To characterise the effects of Mras on cell pluripotency and differentiation, we used gain-and loss-of-function strategies in mESCs and in the Xenopus laevis embryo, in which Mras gene structure and protein sequence are conserved. We show that persistent knockdown of Mras in mESCs reduces expression of specific master genes and that MRAS plays a crucial role in the downregulation of OCT4 and NANOG protein levels upon differentiation. In Xenopus, we demonstrate the potential of Mras to modulate cell fate at early steps of development and during neurogenesis. Overexpression of Mras allows gastrula cells to retain responsiveness to fibroblast growth factor (FGF) and activin. Collectively, these results highlight novel conserved and pleiotropic effects of MRAS in stem cells and early steps of development.

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MRAS in coronary artery disease—Unchartered territory

Shah,

Reinberger,

Hashmi

et al. 2024

IUBMB Life

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Genome‐wide association studies (GWAS) have identified coronary artery disease (CAD) susceptibility locus on chromosome 3q22.3. This locus contains a cluster of several genes that includes muscle rat sarcoma virus (MRAS). Common MRAS variants are also associated with CAD causing risk factors such as hypertension, dyslipidemia, obesity, and type II diabetes. The MRAS gene is an oncogene that encodes a membrane‐bound small GTPase. It is involved in a variety of signaling pathways, regulating cell differentiation and cell survival (mitogen‐activated protein kinase [MAPK]/extracellular signal‐regulated kinase and phosphatidylinositol 3‐kinase) as well as acute phase response signaling (tumor necrosis factor [TNF] and interleukin 6 [IL6] signaling). In this review, we will summarize the role of genetic MRAS variants in the etiology of CAD and its comorbidities with the focus on tissue distribution of MRAS isoforms, cell type/tissue specificity, and mode of action of single nucleotide variants in MRAS associated complex traits. Finally, we postulate that CAD risk variants in the MRAS locus are specific to smooth muscle cells and lead to higher levels of MRAS, particularly in arterial and cardiac tissue, resulting in MAPK‐dependent tissue hypertrophy or hyperplasia.

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M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation

Cited by 32 publications

References 65 publications

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate

MRAS in coronary artery disease—Unchartered territory

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