Kidney Res Clin Pract.  2012 Jun;31(2):94-105.

TGF-beta-activated kinase-1: New insights into the mechanism of TGF-beta signaling and kidney disease

• Kim SI
• Choi ME

Abstract

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates a wide variety of cellular functions, including cell growth, cellular differentiation, apoptosis, and wound healing. TGF-beta1, the prototype member of the TGF-beta superfamily, is well established as a central mediator of renal fibrosis. In chronic kidney disease, dysregulation of expression and activation of TGF-beta1 results in the relentless synthesis and accumulation of extracellular matrix proteins that lead to the development of glomerulosclerosis and tubulointerstitial fibrosis, and ultimately to end-stage renal disease. Therefore, specific targeting of the TGF-beta signaling pathway is seemingly an attractive molecular therapeutic strategy in chronic kidney disease. Accumulating evidence demonstrates that the multifunctionality of TGF-beta1 is connected with the complexity of its cell signaling networks. TGF-beta1 signals through the interaction of type I and type II receptors to activate distinct intracellular pathways. Although the Smad signaling pathway is known as a canonical pathway induced by TGF-beta1, and has been the focus of many previous reviews, importantly TGF-beta1 also induces various Smad-independent signaling pathways. In this review, we describe evidence that supports current insights into the mechanism and function of TGF-beta-activated kinase 1 (TAK1), which has emerged as a critical signaling molecule in TGF-beta-induced Smad-independent signaling pathways. We also discuss the functional role of TAK1 in mediating the profibrotic effects of TGF-beta1.

Keyword

Chronic kidney disease; Fibrosis; Intracellular signaling; Transforming growth factor-beta1; Transforming growth factor-beta-activated kinase 1

MeSH Terms

Apoptosis
Extracellular Matrix Proteins
Fibrosis
Kidney
Kidney Diseases
Kidney Failure, Chronic
MAP Kinase Kinase Kinases
Negotiating
Phosphotransferases
Renal Insufficiency, Chronic
Transforming Growth Factor beta
Transforming Growth Factor beta1
Wound Healing
Extracellular Matrix Proteins
MAP Kinase Kinase Kinases
Phosphotransferases
Transforming Growth Factor beta
Transforming Growth Factor beta1