PDZK1-interacting protein 1 (PDZK1IP1) traps Smad4 protein and suppresses transforming growth factor-β (TGF-β) signaling

Abstract

Edited by Xiao-Fan WangTransforming growth factor (TGF)-␤ signaling in humans is stringently regulated to prevent excessive TGF-␤ signaling. In tumors, TGF-␤ signaling can both negatively and positively regulate tumorigenesis dependent on tumor type, but the reason for these opposite effects is unclear. TGF-␤ signaling is mainly mediated via the Smad-dependent pathway, and herein we found that PDZK1-interacting protein 1 (PDZK1IP1) interacts with Smad4. PDZK1IP1 inhibited both the TGF-␤ and the bone morphogenetic protein (BMP) pathways without affecting receptor-regulated Smad (R-Smad) phosphorylation. Rather than targeting R-Smad phosphorylation, PDZK1IP1 could interfere with TGF-␤-and BMP-induced R-Smad/Smad4 complex formation. Of note, PDZK1IP1 retained Smad4 in the cytoplasm of TGF-␤-stimulated cells. To pinpoint PDZK1IP1's functional domain, we created several PDZK1IP1 variants and found that its middle region, from Phe 40 to Ala 49 , plays a key role in its Smad4-regulating activity. PDZK1IP1 knockdown enhanced the expression of the TGF-␤ target genes Smad7 and prostate transmembrane protein androgen-induced (TMEPAI) upon TGF-␤ stimulation. In contrast, PDZK1IP1 overexpression suppressed TGF-␤-induced reporter activities, cell migration, and cell growth inhibition. In a xenograft tumor model in which TGF-␤ was previously shown to elicit tumor-promoting effects, PDZK1IP1 gain of function decreased tumor size and increased survival rates. Taken together, these findings indicate that PDZK1IP1 interacts with Smad4 and thereby suppresses the TGF-␤ signaling pathway.

Identification of Hub Genes Associated With Hepatocellular Carcinoma Using Robust Rank Aggregation Combined With Weighted Gene Co-expression Network Analysis

“…For example, exosome hsa-miR-335 was identified as a therapeutic target for HCC ( Wang F. et al, 2018 ). Furthermore, according to web-based KEGG analysis, this network is enriched in multiple tumor-related pathways ( Supplementary Table 7 ), such as cell cycle and p53 signaling ( Hussain et al, 2007 ; Sanchez-Vega et al, 2018 ; Ikeno et al, 2019 ). Thus our group of hub genes may play important roles in HCC through the miRNA–mRNA regulatory network.…”

“…To explore the functions of this group of genes from the global network, miRNA–mRNA regulatory networks were generated using miRNet ( Figure 4 ). As shown in Supplementary Table 7 , specific pathways, such as cell cycle, and p53 signaling, were highlighted, both of which are closely related to tumorigenesis and the development of HCC ( Hussain et al, 2007 ; Sanchez-Vega et al, 2018 ; Ikeno et al, 2019 ). Importantly, we used TCGA-LIHC, a dataset containing 374 HCC samples, to validate the predictive power of these hub genes in the progression and prognosis of HCC.…”

Identification of Fibroblast Activation Protein as an Osteogenic Suppressor and Anti-osteoporosis Drug Target

“…Zbtb40, a transcription factor that promotes osteogenesis and inhibits osteoclastogenesis (Mei et al, 2019), was significantly upregulated after FAPi administration (Figure 4A). In contrast, suppressors of osteogenesis such as Foxp2 and Pdzk1ip1 (Ikeno et al, 2019;Zhao et al, 2015) were significantly downregulated after FAPi administration (Figure 4A). Gene Ontology (GO) analysis showed significant enrichment of genes related to cell proliferation and ossification after FAPi administration (Figures 4B-4D).…”

SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis

“…By acting as a central intracellular effector and final downstream component, SMAD4 plays an essential role in TGF-β signal transduction 3,4 . Loss or deficiency of SMAD4 not only inactivates TGF-β signaling, but also impairs TGF-β-mediated transcriptional regulation and biological functions 5,6 . Studies using conditional Smad4 knockout (Smad4-KO) mouse models have revealed that loss of SMAD4 can decrease the sensitivity of tissues or cells to TGF-β1 7,8 .…”