1 pMad Local Model In our analysis, transmission of BMP signal from membrane to nucleus through Smad phosphorylation is approximated by Eq. 1. More detailed networks on nucleocytoplasmic shuttling of Smad and their downstream interpretations are given in (1). The Smad network model we consider here for signal transduction is represented using a 1 order differential equation, that includes phosp...

BACKGROUND Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification. METHODS AND RESULTS Human calcified AVs obtained fr...

Smad2, Smad3 and Smad4 proteins are considered to be key mediators of transforming growth factor-beta (TGF-beta) signaling. However, the identities of the Smad partners mediating TGF-beta signaling are not fully understood. Here, we show that RNA-binding protein with multiple splicing (RBPMS), a member of the RNA-binding protein family, physically interacts with Smad2, Smad3 and Smad4 both in v...

Despite advances in radiation delivery protocols, exposure of normal tissues during the course of radiation therapy remains a limiting factor of cancer treatment. If the canonical TGF-β/Smad pathway has been extensively studied and implicated in the development of radiation damage in various organs, the precise modalities of its activation following radiation exposure remain elusive. In the pre...

Smad proteins are critical intracellular mediators of the transforming growth factor-beta, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-Smads are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-Smads then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with va...

TGF-beta and BMP receptor kinases activate Smad transcription factors by C-terminal phosphorylation. We have identified a subsequent agonist-induced phosphorylation that plays a central dual role in Smad transcriptional activation and turnover. As receptor-activated Smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by CDK8 and CDK9, which are componen...

Runx factors control lineage commitment and are transcriptional effectors of Smad signaling. Genetic defects in these pathways interfere with normal development. The in situ localization of Runx and Smad proteins must impact the mechanisms by which these proteins function together in gene regulation. We show that the integration of Runx and Smad signals is mediated by in situ interactions at sp...

Liu, Lan, Rachel Santora, Jaladanki N. Rao, Xin Guo, Tongtong Zou, Huifang M. Zhang, Douglas J. Turner, and Jian-Ying Wang. Activation of TGF-Smad signaling pathway following polyamine depletion in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 285: G1056–G1067, 2003. First published July 10, 2003; 10.1152/ajpgi.00151.2003.—Smad proteins are transcription activators that a...

INTRODUCTION Erectile dysfunction (ED) in patients with diabetes mellitus (DM) seriously affects their quality of life. However, these patients show a poor effect rate for oral phosphodiesterase type 5 inhibitors. Thus, new treatment methods are urgently needed. Fingolimod hydrochloride (FTY720) was approved in 2010 for the treatment of patients with the relapsing-remitting form of multiple scl...