Roles for the type III TGF-beta receptor in human cancer

Abstract

Transforming growth factor beta (TGF-beta) superfamily ligands have important roles in regulating cellular homeostasis, embryonic development, differentiation, proliferation, immune surveillance, angiogenesis, motility, and apoptosis in a cell type and context specific manner. TGF-beta superfamily signaling pathways also have diverse roles in human cancer, functioning to either suppress or promote cancer progression. The TGF-beta superfamily co-receptor, the type III TGF-beta receptor (TbetaRIII, also known as betaglycan) mediates TGF-beta superfamily ligand dependent as well as ligand independent signaling to both Smad and non-Smad signaling pathways. Loss of TbetaRIII expression during cancer progression and direct effects of TbetaRIII on regulating cell migration, invasion, proliferation, and angiogenesis support a role for TbetaRIII as a suppressor of cancer progression and/or as a metastasis suppressor. Defining the physiological function and mechanism of TbetaRIII action and alterations in TbetaRIII function during cancer progression should enable more effective targeting of TbetaRIII and TbetaRIII mediated functions for the diagnosis and treatment of human cancer.

Figure 1

TβRIII Structure. TβRIII consists of a large extracellular domain (ECD), which has multiple sites of glycan modification (proteoglycan and glycosylation), a hydrophobic transmembrane domain, and a short cytoplasmic domain, which interacts with β-arrestin2 via phosphorylation of amino acid site 841, and with GIPC via the PDZ domain.

Figure 2

TβRIII mediates both ligand dependent and independent effects. A. TβRIII can mediate cell migration in a β-arrestin2 dependent manner through the activation of Cdc42 in a ligand independent manner. TβRIII activates p38 in both a ligand independent and dependent manner. TβRIII undergoes ectodomain shedding producing soluble TβRIII, which can bind to and sequester ligand, inhibiting TGF-β signaling. B. TβRIII presents ligand to TβRII, which phosphorylates TβRIII, and recruits and phosphorylates TβRI, causing phosphorylation of the R-Smads. Phosphorylation of the R-Smads allows interaction with co-Smad4, mediating nuclear translocation of the Smad complex and regulation of transcriptional activity. Interaction of TβRIII with β-arrestin2 results in the internalization of the TβRIII/TβRII/β-arrestin2 complex and subsequent down-regulation of TGF-β signaling. TβRIII also negatively regulates NF B signaling in a β-arrestin2 dependent manner. Interaction of TβRIII with GIPC stabilizes TβRIII at the cell membrane and enhances TGF-β signaling, as well as mediating effects on migration and invasion.

Figure 3

TβRIII Regulates BMP Mediated Signaling. A. TβRIII binds to inhibin and promotes the binding of inhibin to the type II receptor. The binding of inhibin to the type II receptor prevents binding of BMP (or activin, not shown) and fails to recruit the type I receptor, antagonizing both BMP (and activin) signaling. B. TβRIII interacts with ALK3 via the extracelluar domain in a β-arrestin2 independent manner and stabilizes ALK3 at the cell surface stimulating ALK3 mediated transcription. C. TβRIII interacts with ALK6 via the extracelluar and cytoplasmic domains in a β-arrestin2 dependent manner. This β-arrestin2- TβRIII-ALK6 complex is internalized and localized to endocytic vesicles, leading to maximal ALK6 mediated BMP signaling.