Altering the Proteoglycan State of Transforming Growth Factor ß Type III Receptor (TßRIII)/Betaglycan Modulates Canonical Wnt/ß-Catenin Signaling.

Hyperactive Wnt/ß-catenin signaling is linked to cancer progression and developmental abnormalities, making identification of mechanisms controlling Wnt/ß-catenin signaling vital. Transforming growth factor ß type III receptor (TßRIII/betaglycan) is a transmembrane proteoglycan co-receptor that exists with or without heparan and/or chondroitin sulfate glycosaminoglycan (GAG) modifications in cells and has established roles in development and cancer. Our studies here demonstrate that TßRIII, independent of its TGFß co-receptor function, regulates canonical Wnt3a signaling by controlling Wnt3a availability through its sulfated GAG chains. Our findings revealed, for the first time, opposing functions for the different GAG modifications on TßRIII suggesting that Wnt interactions with the TßRIII heparan sulfate chains result in inhibition of Wnt signaling, likely via Wnt sequestration, whereas the chondroitin sulfate GAG chains on TßRIII promote Wnt3a signaling. These studies identify a novel, dual role for TßRIII/betaglycan and define a key requirement for the balance between chondroitin sulfate and heparan sulfate chains in dictating ligand responses with implications for both development and cancer.

Dually modified transmembrane proteoglycans in development and disease.

Aberrant cell signaling in response to secreted growth factors has been linked to the development of multiple diseases, including cancer. As such, understanding mechanisms that control growth factor availability and receptor-growth factor interaction is vital. Dually modified transmembrane proteoglycans (DMTPs), which are classified as cell surface macromolecules composed of a core protein decorated with covalently linked heparan sulfated (HS) and/or chondroitin sulfated (CS) glycosaminoglycan (GAG) chains, provide one type of regulatory mechanism. Specifically, DMTPs betaglycan and syndecan-1 (SDC1) play crucial roles in modulating key cell signaling pathways, such as Wnt, transforming growth factor-ß and fibroblast growth factor signaling, to affect epithelial cell biology and cancer progression. This review outlines current and potential functions for betaglycan and SDC1, with an emphasis on comparing individual roles for HS and CS modified DMTPs. We highlight the mutual dependence of DMTPs' GAG chains and core proteins and provide comprehensive knowledge on how these DMTPs, through regulation of ligand availability and receptor internalization, control cell signaling pathways involved in development and disease.

Inhibin Is a Novel Paracrine Factor for Tumor Angiogenesis and Metastasis.

Inhibin is a heterodimeric TGFß family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers; however, its tumor-specific functions remain unknown. Here, we demonstrate that the α subunit of inhibin (INHA), which is critical for the functionality of dimeric inhibin A/B, correlates with microvessel density in human ovarian tissues and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that inhibin-regulated angiogenesis is necessary for metastasis. Although inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo Inhibin-induced angiogenesis was abrogated via anti-inhibin α antibodies. The endothelial-specific TGFß receptor complex comprising ALK1 and endoglin was a crucial mediator of inhibin signaling, offering a molecular mechanism for inhibin-mediated angiogenesis. These results are the first to define a role for inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting inhibin therapeutically.Significance: Inhibin is a predictor of poor patient survival in multiple cancers and is a potential target for antiangiogenic therapies. Cancer Res; 78(11); 2978-89. ©2018 AACR.

Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer.

CDK8 is a transcription-regulating kinase that controls TGF-ß/BMP-responsive SMAD transcriptional activation and turnover through YAP1 recruitment. However, how the CDK8/YAP1 pathway influences SMAD1 response in cancer remains unclear. Here we report that SMAD1-driven epithelial-to-mesenchymal transition (EMT) is critically dependent on matrix rigidity and YAP1 in a wide spectrum of cancer models. We find that both genetic and pharmacological inhibition of CDK8 and its homologous twin kinase CDK19 leads to abrogation of BMP-induced EMT. Notably, selectively blocking CDK8/19 specifically abrogates tumor cell invasion, changes in EMT-associated transcription factors, E-cadherin expression and YAP nuclear localization both in vitro and in vivo in a murine syngeneic EMT model. Furthermore, RNA-seq meta-analysis reveals a direct correlation between CDK8 and EMT-associated transcription factors in patients. Our findings demonstrate that CDK8, an emerging therapeutic target, coordinates growth factor and mechanical cues during EMT and invasion.

TGF-ß triggers rapid fibrillogenesis via a novel TßRII-dependent fibronectin-trafficking mechanism.

Fibronectin (FN) is a critical regulator of extracellular matrix (ECM) remodeling through its availability and stepwise polymerization for fibrillogenesis. Availability of FN is regulated by its synthesis and turnover, and fibrillogenesis is a multistep, integrin-dependent process essential for cell migration, proliferation, and tissue function. Transforming growth factor ß (TGF-ß) is an established regulator of ECM remodeling via transcriptional control of ECM proteins. Here we show that TGF-ß, through increased FN trafficking in a transcription- and SMAD-independent manner, is a direct and rapid inducer of the fibrillogenesis required for TGF-ß-induced cell migration. Whereas TGF-ß signaling is dispensable for rapid fibrillogenesis, stable interactions between the cytoplasmic domain of the type II TGF-ß receptor (TßRII) and the FN receptor (α5ß1 integrin) are required. We find that, in response to TGF-ß, cell surface-internalized FN is not degraded by the lysosome but instead undergoes recycling and incorporation into fibrils, a process dependent on TßRII. These findings are the first to show direct use of trafficked and recycled FN for fibrillogenesis, with a striking role for TGF-ß in this process. Given the significant physiological consequences associated with FN availability and polymerization, our findings provide new insights into the regulation of fibrillogenesis for cellular homeostasis.