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

组织结构由底层结缔组织维持。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，其中包括胶原蛋白）组成。结缔组织内的成纤维细胞，负责细胞外基质的产生和重塑，因此具有结缔组织的功能。作为对损伤的反应，一种分化成纤维细胞，肌成纤维细胞（之所以被称为肌成纤维细胞，是因为它表达高度收缩的α -平滑肌肌动蛋白），负责产生和重塑新的ECM；肌成纤维细胞在正常修复过程中消失，但在疤痕（纤维化）组织中不正常。了解成纤维细胞如何促进皮肤稳态和修复，不仅对了解成纤维细胞功能和皮肤稳态至关重要，而且对如何正确地设计替代皮肤组织至关重要，使其与正常组织融合而不收缩（即不留下疤痕）。细胞因子转化生长因子(TGF) β可通过典型途径和非典型途径诱导成纤维细胞产生和重塑ECM，后者涉及通过整合素β 1和局灶粘附激酶（FAK）操作的粘附信号。成纤维细胞丢失整合素β 1导致肌成纤维细胞形成受损和组织修复动力学延迟。此外，在活化的真皮成纤维细胞中，磷酸酶PTEN（磷酸酶和紧张素同源物）的表达减少，该酶通过去磷酸化FAK来灭活粘附信号；真皮成纤维细胞PTEN表达的缺失显著增加了体内真皮厚度，提高了成纤维细胞在体内和体外的ECM生成和收缩反应。tgf β活化激酶（TAK）1通路在FAK下游作用，促进ECM重构以响应tgf β。TAK1在成纤维细胞中的表达是维持正常皮肤厚度和诱导肌成纤维细胞响应组织损伤所必需的。这种非典型的TGF β通路似乎特异性地控制对TGF β的收缩反应。然而，粘附/TAK1介导成纤维细胞产生和重塑ECM能力的基本信号机制尚不清楚。我们还发现，积极进行ECM产生/重塑的成纤维细胞具有整合素β 1介导的ROS生成，这是参与ECM产生和重塑的基因表达所必需的。总的来说，这些数据提示了一个有趣的想法，即成纤维细胞积极参与ECM重塑以响应TGF β等因子的能力是通过粘附信号/TAK/ ros依赖机制发生的。然而，这一假设尚未得到评估，是本提案的主题。

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.