Biogenesis and function of fibrillin assemblies.
Biogenesis and function of fibrillin assemblies.
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DOI：
10.1007/s00441-009-0822-x
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发表时间：
2010-01
影响因子：
3.6
通讯作者：
Sakai, Lynn Y.
中科院分区：
文献类型：
--
作者：
Ramirez, Francesco;Sakai, Lynn Y.
纤颤蛋白1和纤颤蛋白2是富含半胱氨酸的大型糖蛋白，具有两种关键的生理功能：作为维持组织完整性的支持结构和作为指导细胞性能的信号事件的调节剂。纤维蛋白的结构作用是通过微纤维和弹性纤维的时间和层次组装发挥作用，而指导性作用则反映了纤维蛋白在细胞外基质中隔离转化生长因子β (TGFβ)和骨形态发生蛋白（BMP）复合物的能力。人类患者和基因工程小鼠中纤维蛋白突变的表征表明，任何一种功能的扰动都表现在疾病中。更一般地说，这些研究表明，纤原蛋白是细胞外、细胞表面和信号分子组成的更广泛的生物网络的组成部分，这些生物网络协调了多器官系统的形态发生和稳态程序。他们还提出，富含纤维蛋白的微原纤维的相对组成赋予了TGFβ和BMP信号的语境特异性，通过局部集中配体来调节器官形成过程中空间背景下的细胞分化（正调节），并通过限制其生物利用度来及时调节组织重塑/修复过程中的细胞性能（负调节）。相关证据表明微原纤维的细胞定向组装和TGFβ和BMP复合物靶向纤维蛋白的功能偶联。因此，新出现的观点是，富含纤维蛋白的微原纤维是结构和指向性信号的分子整合者，TGFβ和bmp是将细胞外输入转化为离散的和依赖环境的细胞反应的节点。
Fibrillin-1 and fibrillin-2 are large cysteine-rich glycoproteins that serve two key physiological functions: as supporting structures that impart tissue integrity and as regulators of signaling events that instruct cell performance. The structural role of fibrillins is exerted through the temporal and hierarchical assembly of microfibrils and elastic fibers, whereas the instructive role reflects the ability of fibrillins to sequester transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) complexes in the extracellular matrix. Characterization of fibrillin mutations in human patients and in genetically engineered mice has demonstrated that perturbation of either function manifests in disease. More generally, these studies have indicated that fibrillins are integral components of a broader biological network of extracellular, cell surface, and signaling molecules that orchestrate morphogenetic and homeostatic programs in multiple organ systems. They have also suggested that the relative composition of fibrillin-rich microfibrils imparts contextual specificity to TGFβ and BMP signaling by concentrating the ligands locally so as to regulate cell differentiation within a spatial context during organ formation (positive regulation) and by restricting their bioavailability so as to modulate cell performance in a timely fashion during tissue remodeling/ repair (negative regulation). Correlative evidence suggests functional coupling of the cell-directed assembly of micro-fibrils and targeting of TGFβ and BMP complexes to fibrillins. Hence, the emerging view is that fibrillin-rich microfibrils are molecular integrators of structural and instructive signals, with TGFβ and BMPs as the nodal points that convert extracellular inputs into discrete and context-dependent cellular responses.
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