The tale of transforming growth factor-beta (TGFβ) signaling: A soigné enigma

Objective: Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires wall thickening with deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as lumen dilation. TAK1 (TGFβ [transforming growth factor-beta]–activated kinase 1) is a mediator of noncanonical TGFβ signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening and lumen dilation during AVF maturation. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm 2 ) activated noncanonical TGFβ signaling including TAK1 phosphorylation in mouse endothelial cells. Conclusions: TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFβ signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.

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Transforming growth factor beta signaling and decidual integrity in mice†

Biology of Reproduction ◽

10.1093/biolre/ioaa155 ◽

2020 ◽

Vol 103 (6) ◽

pp. 1186-1198

Author(s):

Xin Fang ◽

Nan Ni ◽

Yang Gao ◽

John P Lydon ◽

Ivan Ivanov ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Female Reproductive Tract ◽

Molecular Properties ◽

Conditional Knockout ◽

Decidual Cell ◽

Tgfβ Signaling ◽

Growth Factor Beta

Abstract Transforming growth factor beta (TGFβ) signaling regulates multifaceted reproductive processes. It has been shown that the type 1 receptor of TGFβ (TGFBR1) is indispensable for female reproductive tract development, implantation, placental development, and fertility. However, the role of TGFβ signaling in decidual development and function remains poorly defined. Our objective is to determine the impact of uterine-specific deletion of Tgfbr1 on decidual integrity, with a focus on the cellular and molecular properties of the decidua during development. Our results show that the developmental dynamics of the decidua is altered in TGFBR1 conditionally depleted uteri from embryonic day (E) 5.5 to E8.5, substantiated by downregulation of genes associated with inflammatory responses and uterine natural killer cell abundance, reduced presence of nondecidualized fibroblasts in the antimesometrial region, and altered decidual cell development. Notably, conditional ablation of TGFBR1 results in the formation of decidua containing more abundant alpha smooth muscle actin (ACTA2)-positive cells at the peripheral region of the antimesometrial side versus controls at E6.5–E8.5. This finding is corroborated by upregulation of a subset of smooth muscle marker genes in Tgfbr1 conditionally deleted decidua at E6.5 and E8.5. Moreover, increased cell proliferation and enhanced decidual ERK1/2 signaling were found in Tgfbr1 conditional knockout mice upon decidual regression. In summary, conditional ablation of TGFBR1 in the uterus profoundly impacts the cellular and molecular properties of the decidua. Our results suggest that TGFBR1 in uterine epithelial and stromal compartments is important for the integrity of the decidua, a transient but crucial structure that supports embryo development.

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T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ) signaling mediate superior tumor regression in an animal model of adoptive cell therapy

Journal of Translational Medicine ◽

10.1186/1479-5876-10-127 ◽

2012 ◽

Vol 10 (1) ◽

pp. 127 ◽

Cited By ~ 20

Author(s):

Jon G Quatromoni ◽

Yue Wang ◽

Dan D Vo ◽

Lilah F Morris ◽

Ali R Jazirehi ◽

...

Keyword(s):

Animal Model ◽

Growth Factor ◽

T Cell Receptor ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Tumor Regression ◽

Adoptive Cell Therapy ◽

Cell Receptor ◽

Tgfβ Signaling ◽

Growth Factor Beta

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Structural biology of the TGFβ family

Experimental Biology and Medicine ◽

10.1177/1535370219880894 ◽

2019 ◽

Vol 244 (17) ◽

pp. 1530-1546 ◽

Cited By ~ 3

Author(s):

Erich J Goebel ◽

Kaitlin N Hart ◽

Jason C McCoy ◽

Thomas B Thompson

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Structural Biology ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Biological Processes ◽

Tgfβ Signaling ◽

Growth Factor Beta ◽

Tgfβ Signaling Pathway

The transforming growth factor beta (TGFβ) signaling pathway orchestrates a wide breadth of biological processes, ranging from bone development to reproduction. Given this, there has been a surge of interest from the drug development industry to modulate the pathway – at several points. This review discusses and provides additional context for several layers of the TGFβ signaling pathway from a structural biology viewpoint. The combination of structural techniques coupled with biophysical studies has provided a foundational knowledge of the molecular mechanisms governing this high impact, ubiquitous pathway, underlying many of the current therapeutic pursuits. This work seeks to consolidate TGFβ-related structural knowledge and educate other researchers of the apparent gaps that still prove elusive. We aim to highlight the importance of these structures and provide the contextual information to understand the contribution to the field, with the hope of advancing the discussion and exploration of the TGFβ signaling pathway. Impact statement The transforming growth factor beta (TGFβ) signaling pathway is a multifacetted and highly regulated pathway, forming the underpinnings of a large range of biological processes. Here, we review and consolidate the key steps in TGFβ signaling using literature rooted in structural and biophysical techniques, with a focus on molecular mechanisms and gaps in knowledge. From extracellular regulation to ligand–receptor interactions and intracellular activation cascades, we hope to provide an introductory base for understanding the TGFβ pathway as a whole.

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