TRAF4 Promotes TGF-β Receptor Signaling and Drives Breast Cancer Metastasis

Son

Proc. Natl. Acad. Sci. U.S.A.

et al. 2017

Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4), an adaptor protein with E3-ligase activity, is involved in embryogenesis, cancer initiation and progression, and platelet receptor (GPIb-IX-V complex and GPVI)-mediated signaling for reactive oxygen species (ROS) production that initiates thrombosis at arterial shears. Disruption of platelet receptors and the TRAF4 interaction is a potential target for therapeutic intervention by antithrombotic drugs. Here, we report a crystal structure of TRAF4 (amino acid residues 290∼470) in complex with a peptide from the GPIbβ receptor (amino acid residues 177∼181). The GPIbβ peptide binds to a unique shallow surface composed of two hydrophobic pockets on TRAF4. Further studies revealed the TRAF4-binding motif Arg-Leu-X-Ala. The TRAF4-binding motif was present not only in platelet receptors but also in the TGF-β receptor. The current structure will provide a template for furthering our understanding of the receptor-binding specificity of TRAF4, TRAF4-mediated signaling, and related diseases.T he glycoprotein (GP) Ib-IX-V complex and GPVI are two major platelet receptors that mediate the initial adhesion of platelets to the injured vascular wall for initiating thrombus formation, and they are involved in thrombotic diseases such as stroke and myocardial infarction (1, 2). GPVI is known as a primary collagen receptor, while the GP Ib-IX-V complex binds to the von Willebrand factor and diverse ligands including coagulation factor XI (FXI), factor XII, thrombin, and P-selectin (3, 4). The existence of various ligands of the GP Ib-IX-V complex indicates that this receptor complex governs platelet function via multiple signaling pathways (5). The GP Ib-IX-V complex, consisting of GPIbα (the major ligand-binding subunit), GPIbβ, GPIX, and GPV, is the second most abundant receptor in platelets and is physically and functionally linked to another platelet receptor, GPVI (3).Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4) is one of the seven identified TRAF1∼TRAF7 factors in mammals and was initially identified as a regulator of embryogenesis in mice, especially in the central and peripheral nervous system (6). TRAF4 is involved in gross tracheal, neural tube, and skeletal formation (7-9). The involvement of TRAF4 in the initiation and progression of many types of cancer has also been reported, suggesting that TRAF4 is a tentative therapeutic target for cancer treatment (10, 11). Unlike other TRAF family members, TRAF4 contains a nuclear localization signal (NLS) and does not interact with canonical TRAF-binding receptors such as TNFR2, CD30, and CD40, indicating that TRAF4 is not involved in cellular signaling that is mediated by the typical TRAF family (12, 13).Because of the critical function of the TRAF family in various signaling events, including immunity, inflammation, and apoptosis, these have been the main focus of functional, structural, and biochemical analyses of these proteins (13). Intensive study has revealed that the TRAF family, except...

Section: Detailed Traf4-gpibβ Interaction Mode and Its Comparison Withsupporting

confidence: 86%

mentioning

confidence: 96%

Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI

Son

Proc. Natl. Acad. Sci. U.S.A.

et al. 2017

Cold Spring Harb Perspect Biol

“…p38 is an important mediator of TGF-b-induced apoptosis and EMT. Another member of the TRAF family (i.e., TRAF4), has also been implicated in the activation of TAK1 (Zhang et al 2013a). As TAK1 signaling is primed, TRAF4 ubiquitylates Smurf2 and promotes recruitment of the USP15 deubiquitylase, causing TbRI stabilization and enhanced TGF-b signaling (Zhang et al 2013a).…”

Section: Signaling Via Smad and Non-smad Pathwaysmentioning

confidence: 99%

“…Another member of the TRAF family (i.e., TRAF4), has also been implicated in the activation of TAK1 (Zhang et al 2013a). As TAK1 signaling is primed, TRAF4 ubiquitylates Smurf2 and promotes recruitment of the USP15 deubiquitylase, causing TbRI stabilization and enhanced TGF-b signaling (Zhang et al 2013a). An additional ubiquitin ligase, Xlinked inhibitor of apoptosis (XIAP) associates with the TbRI in breast cancer cells and promotes ubiquitylation of TAK1, which then activates nuclear factor kB (NF-kB) transcriptional activity (Neil et al 2009).…”

Section: Signaling Via Smad and Non-smad Pathwaysmentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

512

455

Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

“…It has been reported that various ubiquitin ligases play important roles in the degradation of TGF-b receptors and Smads through the ubiquitin-proteasome pathway. By contrast, the SUMO ligases are responsible for stabilising TGF-b receptors and Smads 10,11 .…”

mentioning

confidence: 99%

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

et al. 2015

Altered transforming growth factor-b (TGF-b) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-b1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-b1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.