由致病性RIT1引起的RAS-依赖RAF-MAPK过活化是Noonan综合征相关心脏缩的治疗标
Antonio Cuevas-Navarro1, Morgan Wagner2, Richard Van1
1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Science advances
|July 14, 2023
概括
突变的RIT1蛋白直接激活RAF激酶,在癌症和努南综合征中驱动MAPK信号. 在小鼠模型中,抑制这种途径减少了心脏缩.
科学领域:
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
- 遗传学 遗传学 是一个
背景情况:
- RIT1 (RAS相互作用蛋白1) 是一种参与信号转导的GTPase.
- 在RIT1中发生的突变与肺癌,白血病和努南综合征有关.
- 致病性RIT1蛋白质导致基激活蛋白激酶 (MAPK) 途径的过激活,但机制尚不清楚.
研究的目的:
- 阐明突变RIT1激活MAPK信号的机制.
- 为了确定膜结合突变RIT1.1的直接影响者.
- 探索针对RIT1-MAPK轴的治疗策略.
主要方法:
- 研究了RIT1和RAF激酶之间的相互作用.
- 在RIT1中确定了膜脂相互作用和RAF结合的关键残留物.
- 利用RIT1突变诺南综合征的小鼠模型来评估途径抑制.
主要成果:
- RAF激酶是膜结合突变RIT1的直接作用者,调解MAPK激活.
- 特定的RIT1残留物对于膜协会,RAF相互作用和MAPK信号传递至关重要.
- 突变RIT1与RAF激酶结合是没有经典RAS蛋白质就不足以激活MAPK.
- 在Noonan综合征小鼠模型中,RAF/MAPK通路的抑制改善了心脏缩.
结论:
- 突变RIT1直接激活RAF激酶,代表了RIT1相关疾病的关键机制.
- 了解RIT1与RAF激酶和膜脂质的相互作用,可以了解疾病的发病性.
- 针对RAF/MAPK通路为RIT1驱动的疾病 (如努南综合征) 提供了潜在的治疗方法.
相关概念视频
01:07MAPK Signaling Cascades
5.7K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.7K
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
465
The activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) contributes to cardiac remodeling, and inhibiting the RAAS is a pharmacological target in heart failure management. As a result, neurohumoral modulation is a crucial treatment principle for managing heart failure. This approach involves using medications like ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, mineralocorticoid receptor antagonists (MRAs), and neutral...
465
02:38The Ras Gene
6.3K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
6.3K
01:22PI3K/mTOR/AKT Signaling Pathway
3.7K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.7K
01:27Transducer Mechanism: Enzyme-Linked Receptors
2.5K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.5K
01:19Interactions Between Signaling Pathways
6.3K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K