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DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation.

ABSTRACT: Ras activates Raf, leading to the extracellular-regulated kinase (ERK)-mitogen-activated protein kinase pathway, which is involved in a variety of cellular, physiological, and pathological responses. Thus, regulators of this Ras-Raf interaction play crucial roles in these responses. In this study, we report a novel regulator of the Ras-Raf interaction named DA-Raf1. DA-Raf1 is a splicing isoform of A-Raf with a wider tissue distribution than A-Raf. It contains the Ras-binding domain but lacks the kinase domain, which is responsible for activation of the ERK pathway. As inferred from its structure, DA-Raf1 bound to activated Ras as well as M-Ras and interfered with the ERK pathway. The Ras-ERK pathway is essential for the negative regulation of myogenic differentiation induced by growth factors. DA-Raf1 served as a positive regulator of myogenic differentiation by inducing cell cycle arrest, the expression of myogenin and other muscle-specific proteins, and myotube formation. These results imply that DA-Raf1 is the first identified competent, intrinsic, dominant-negative antagonist of the Ras-ERK pathway.

SUBMITTER: Yokoyama T

PROVIDER: S-EPMC2064279 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation.

Yokoyama Takashi T Takano Kazunori K Yoshida Akira A Katada Fumiko F Sun Peng P Takenawa Tadaomi T Andoh Toshiwo T Endo Takeshi T

The Journal of cell biology 20070529 5

Ras activates Raf, leading to the extracellular-regulated kinase (ERK)-mitogen-activated protein kinase pathway, which is involved in a variety of cellular, physiological, and pathological responses. Thus, regulators of this Ras-Raf interaction play crucial roles in these responses. In this study, we report a novel regulator of the Ras-Raf interaction named DA-Raf1. DA-Raf1 is a splicing isoform of A-Raf with a wider tissue distribution than A-Raf. It contains the Ras-binding domain but lacks th ...[more]

PMID: 17535970

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Project description:The enhanced migratory ability of endometrial stromal cells (ESCs) is a key factor in the formation of functional endometrium‑like tissues outside the uterine cavity during endometriosis (EMS). Although accumulating evidence has suggested the importance of microRNAs (miRNAs) in the pathogenesis of EMS, the role of particular miRNAs in the invasiveness of ESCs remain poorly understood. In the present study, the function of miRNAs in the invasiveness of ESCs, along with the associated underlying mechanism involved, were investigated. Initially, the expression patterns of miRNAs in the ectopic and eutopic endometrium isolated from patients with EMS were analyzed using microarray. MicroRNA‑202‑5p (miR‑202) was selected for further study due to its previously reported suppressive effects on the invasion in various types of cancers. The expression of miR‑202 and K‑Ras in eutopic and ectopic endometrioma tissues were detected using reverse transcription‑quantitative PCR, immunohistochemistry and western blotting. The migration and invasion ability of ESCs was determined using wound healing and Transwell invasion assays, respectively. Compared with that from healthy individuals, miR‑202 expression was demonstrated to be lower in the eutopic endometrium from patients with EMS, which was even lower in ectopic endometrium. Functional experiments in primary ESCs revealed that enhanced miR‑202 expression suppressed the cell invasion and migration abilities, which was also accompanied with increased E‑cadherin and reduced N‑cadherin expression in ESCs, suggesting its potentially suppressive role in epithelial‑mesenchymal transition. K‑Ras is a well‑known regulator of the ERK signaling pathway that was shown to be directly targeted and negatively regulated by miR‑202. In addition, K‑Ras expression was found to be upregulated in the ectopic endometrium, where it correlated negatively with that of miR‑202. Knocking down K‑Ras expression mimicked the anti‑invasive effects of miR‑202 overexpression on ESCs, whilst K‑Ras overexpression attenuated the inhibitory role of miR‑202 overexpression in ESC invasion. The K‑Ras/Raf1/MEK/ERK signaling pathway was also blocked by miR‑202 overexpression. These findings suggested that miR‑202 inhibited ESC migration and invasion by inhibiting the K‑Ras/Raf1/MEK/ERK signaling pathway, rendering miR‑202 a candidate for being a therapeutic target for EMS.

Dataset Information

DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation.

Publications

DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation.

Similar Datasets

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