The TAK1/ROS pathway: a mediator of adhesive signaling?

组织结构由下面的结缔组织维持。在皮肤中，结缔组织的结构和组织为表面上皮提供支持，并产生皮肤的弹性和屏障功能。结缔组织主要由细胞外基质(ECM，包括胶原)组成。在结缔组织内，成纤维细胞负责产生和重塑细胞外基质，从而发挥结缔组织的功能。作为对损伤的反应，分化成纤维细胞的一种形式，肌成纤维细胞(因其表达高度收缩的蛋白质α-平滑肌肌动蛋白而被称为肌成纤维细胞)，负责产生和重塑新的ECM；肌成纤维细胞在正常修复期间消失，但在瘢痕(纤维性)组织中异常消失。了解成纤维细胞如何促进真皮的动态平衡和修复，不仅对于了解成纤维细胞的功能和皮肤动态平衡至关重要，而且对于如何正确设计替代皮肤组织也是至关重要的，这些组织应该在不收缩(即不形成疤痕)的情况下整合到正常组织中。细胞因子转化生长因子β通过典型途径和非典型途径有效地诱导成纤维细胞产生和重塑细胞外基质，非典型途径涉及通过整合素β1和粘着斑激酶(FAK)调节的黏附信号。成纤维细胞失去整合素Beta1会导致肌成纤维细胞形成受损和延迟的组织修复动力学。此外，在激活的真皮成纤维细胞中，通过去磷酸化FAK而使黏附信号失活的磷酸酶PTEN(磷酸酶和张力蛋白同源物)的表达减少；真皮成纤维细胞失去PTEN的表达显著增加了体内真皮厚度，并增加了体内和体外成纤维细胞的ECM产生和收缩反应。转化生长因子β激活的激酶(TAK)1途径在FAK下游活动，促进细胞外基质重塑。成纤维细胞表达TAK1是维持正常皮肤厚度和诱导肌成纤维细胞对组织损伤做出反应所必需的。这种非规范的转化生长因子β途径似乎特异性地控制对转化生长因子β的收缩反应。然而，黏附/TAK1介导成纤维细胞产生和重塑细胞外基质的基本信号机制尚不清楚。我们还发现，积极经历ECM产生/重塑的成纤维细胞具有整合素β1介导的ROS产生，这是与ECM产生和重塑相关的基因表达所必需的。综上所述，这些数据提示了一个有趣的观点，即成纤维细胞对转化生长因子β等因素的反应积极参与ECM重塑的能力是通过一种依赖于黏附信号/TAK/ROS的机制实现的。然而，这一假设还没有被评估，并且是这项提议的主题。**

Tissue architecture is maintained by the underlying connective tissue. In skin, the structure and organization of connective tissue provides support for surface epithelia and generates the skin's elasticity and barrier functions. Connective tissue is comprised largely of extracellular matrix (ECM, which includes collagen). Within connective tissue, fibroblasts, which are responsible for producing and remodeling the ECM and hence for connective tissue function. In response to injury, a form of differentiated fibroblast, the myofibroblast (so called as it expresses the highly contractile protein alpha-smooth muscle actin), is responsible for producing and remodeling new ECM; myofibroblasts disappear during normal repair but, in scarred (fibrotic) tissue abnormally. Understanding how fibroblasts contribute to dermal homeostasis and repair is essential not only for understanding fibroblast function and skin homeostasis but also how to properly engineer replacement skin tissue which should integrate within the normal tissue without contractions (i.e., without scarring). The cytokine transforming growth factor (TGF) beta potently induces fibroblasts to produce and remodel ECM via both canonical pathway and non-canonical pathways, the latter of which involves adhesive signaling operating through integrin beta1 and focal adhesion kinase (FAK). Loss of integrin beta1 by fibroblasts results in impaired myofibroblast formation and delayed tissue repair kinetics. Moreover, expression of the phosphatase PTEN (Phosphatase and tensin homolog), which inactivates adhesive signaling by dephosphorylating FAK, is decreased in activated dermal fibroblasts; loss of PTEN expression by dermal fibroblasts significantly increased dermal thickness in vivo and elevated ECM production and contractile responses by fibroblasts both in vivo and in vitro. TGFbeta activated kinase (TAK)1 pathway operates downstream of FAK to promote ECM remodeling in response to TGFbeta. TAK1 expression by fibroblasts is required for maintaining normal skin thickness and for the induction of myofibroblasts in response to tissue injury. This non-canonical TGF beta pathway appears to specifically control contractile responses to TGF beta. However, the fundamental signaling mechanisms through which adhesion/TAK1 mediates the ability of fibroblasts to produce and remodel ECM are unclear. We also showed that fibroblasts actively undergoing ECM production/remodeling have integrin beta 1-mediated ROS generation was required for the expression of genes involved with ECM production and remodeling. Collectively, these data suggest the intriguing idea that the ability of fibroblasts to actively engage in ECM remodeling in response to factors such as TGF beta occurs via an adhesive signaling/TAK/ROS-dependent mechanism. However, this hypothesis has not been evaluated, and is the subject of this proposal. **