Ubiquitin Ligase Nedd4L Targets Activated Smad2/3 to Limit TGF-β Signaling

Abstract

Summary TGFβ induces phosphorylation of the transcription factors Smad2 and Smad3 at the C-terminus as well as at an interdomain linker region. TGFβ-induced linker phosphorylation marks the activated Smad proteins for proteasome-mediated destruction. Here we identify Nedd4L as the ubiquitin ligase responsible for this step. Through its WW domain Nedd4L specifically recognizes a TGFβ-induced phosphoThr-ProTyr motif in the linker region, resulting in Smad2/3 poly-ubiquitination and degradation. Nedd4L is not interchangeable with Smurf1, a ubiquitin ligase that targets BMP-activated, linker-phosphorylated Smad1. Nedd4L limits the half-life of TGFβ activated Smads, restricts the amplitude and duration of TGFβ gene responses, and in mouse embryonic stem cells limits the induction of mesoendodermal fates by Smad2/3-activating factors. Hierarchical regulation is provided by SGK1, which phosphorylates Nedd4L to prevent binding of Smad2/3. Previously identified as a regulator of renal sodium channels, Nedd4L is shown here to play a broader role as a general modulator of Smad turnover during TGFβ signal transduction.

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

“…Diseased valves have been shown previously to express the pleiotropic growth factor, TGF-β1 [32,30,45] and a mouse model of CAVD has demonstrated elevated levels of phosphorylated Smad transcription factors in aortic valves [46]. This study demonstrates that in human aortic valve lesions expression of both TGFβ1 and phosphorylated Smad2/3 are elevated throughout the thickened valve leaflets.…”

Wg Signaling via Zw3 and Mad Restricts Self-Renewal of Sensory Organ Precursor Cells in Drosophila

“…In the larval wing disk, this occurs in vein precursor cells and results in the ectopic veins of MGM and DN-Zw3 wings as well as the loss of veins in CA-Zw3 and MadRNAi wings. This aspect of the Zw3-Mad interaction is consistent with prior studies and is further supported by Gao et al (2009). On the basis of studies in mammalian cells, they identified Nedd4L and Smurf1 as ubiquitin ligases recognizing doubly phosphorylated (Receptor and Gsk3-b) Smad2/3 or Smad1, respectively.…”

TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

“…The linker domain undergoes regulatory phosphorylation by mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), p38 MAPK, and cyclin-dependent kinase (CDK) as well as glycogen synthase kinase 3-b (Fig. 1a, middle) [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”