Dipartimento di Scienze Mediche e Chirurgiche, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1, 25100 Brescia, Italia.
Curr Med Chem. 2012;19(3):454-60. doi: 10.2174/092986712803414286.
The transforming growth factor β (TGFβ) superfamily consists of multipotential secreting cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFβs act as ligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGFβ receptor type I (TGFβRI) and type 2 (TGFβRII), and TGFβRIII receptors which include an ubiquitous extracellular β-glycan and the membrane glycoprotein endoglin (CD105). Binding of TGFβs to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFβ signaling has been implicated in various human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGFβR1 and TGFβR2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/or cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysms and dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGFβ cascade, on the clinical features of LDS, as well as on the mechanisms of TGFβ signaling perturbation leading to this condition and the potential role of the antagonism of TGFβ activity in disease management.
转化生长因子 β（TGFβ）超家族由多种潜能分泌的细胞因子组成，介导正常细胞生长和发育中的许多关键事件，包括分化、增殖、运动、组织和死亡。TGFβs 作为细胞表面受体 3 类的配体，跨膜丝氨酸-苏氨酸激酶受体，TGFβ 受体 I（TGFβRI）和类型 2（TGFβRII）和 TGFβRIII 受体，包括普遍存在的细胞外β-聚糖和膜糖蛋白内格林（CD105）。TGFβs 与其受体结合启动多种细胞反应，导致 Smad 蛋白磷酸化，然后易位到细胞核并调节靶基因的转录。TGFβ 信号转导的扰动与包括癌症、纤维化和自身免疫性疾病在内的各种人类疾病有关。最近，TGFβR1 和 TGFβR2 基因的突变与广泛的血管受累相关的一系列临床特征有关。临床严重程度的极端表现为 Loeys-Dietz 综合征（LDS），这是一种常染色体显性遗传疾病，其特征是眼距过宽、悬雍垂分叉和/或腭裂，以及动脉性动脉病变导致动脉扭曲，以及危及生命的并发症，如血管动脉瘤和夹层。动脉壁中的弹性蛋白排列紊乱、弹性纤维结构丧失和胶原表达增加是 LDS 的病理标志。在本文综述中，我们将详细介绍 TGFβ 级联的激活、LDS 的临床特征，以及导致这种情况的 TGFβ 信号转导扰动机制以及 TGFβ 活性拮抗在疾病管理中的潜在作用。
