TMEFF1 and brain tumors

Gery, Sigal; Ding, Yin; Xie, Dong; Black, Keith L.; Koeffler, H. Phillip

doi:10.1038/sj.onc.1206351

Cited by 23 publications

(27 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…co-localize on the cell membrane surface (27,39) also supports the possible interaction, since mature ST14 is secreted into human milk in a complexed form (9).…”

Section: Discussionmentioning

confidence: 91%

“…Interestingly, matriptase-3, which is 31% identical to ST14, is also expressed at a high level in the brain (40). The expression of TMEFF1 is down-regulated in brain tumors (27), but the relationship between matriptase-3, TMEFF1, and cancer diseases has not been established. ST14 and TMEFF1 are hypothesized as tumor suppressor genes in colon cancers and in brain cancers, respectively (3,27,29,36,41).…”

Section: Discussionmentioning

confidence: 98%

“…These domains implicate a role for TMEFF1 in growth factor signaling (27). Several proteins that participate in the regulation of growth factor signaling, CSF1, IGF2, and TGFA have also been detected at high levels in the cell line RKO-ST14 (36).…”

Section: Discussionmentioning

confidence: 99%

“…Northern blot analysis showed TMEFF1 was expressed at a moderately low level in the prostate cancer cell line PC3 (27). The ST14 mRNA is undetectable in PC3 according to quantitative real time PCR results of Bhatt et al (28), although Takeuchi et al (5) cloned ST14 cDNA from PC3 cells.…”

Section: Gst-st14 Domains As Bait To Capture Preymentioning

confidence: 99%

See 3 more Smart Citations

Protein Interaction Analysis of ST14 Domains and Their Point and Deletion Mutants

Ding

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

ST14 (suppression of tumorigenicity 14) is a transmembrane serine protease that contains a serine protease catalytic (SP) domain, an SEA domain, two complement subcomponent C1r/s (CUB) domains, and four low density lipoprotein receptor class A domains. Glutathione S-transferase fusion proteins with SP, CUB, and low density lipoprotein receptor domains and their corresponding mutants were generated to analyze protein interactions with these domains. Modified glutathione S-transferase pull-down assays demonstrated the interaction between the SP domain and hepatocyte growth factor activator inhibitor-1. With the same method, a CUB domain-interacting protein was isolated and turned out to be the transmembrane protein with epidermal growth factorlike and two follistatin-like domains 1 (TMEFF1). Quantitative real time PCR revealed that the expression of the TMEFF1 gene was dependent on the transfection of the ST14 gene in the RKO cell line. Our results also suggested that ST14 and TMEFF1 were co-expressed in the human breast cancer cell line MCF7, human placenta, kidney, and liver tissues. Interestingly, these two genes were co-upregulated in kidney tumors versus normal tissues, consistent with our results that showed the dependence of TMEFF1 expression on ST14 in RKO cells. Finally, homology modeling studies suggested that TMEFF1 might form a complex with ST14 by an interaction between epidermal growth factor and CUB domains. 14) is a multidomain transmembrane serine protease of the S1 trypsin-like protein family (1). It was first isolated as a novel matrix-degrading protease from human breast cancer cells by Shi et al. (2). Independently by using subtractive hybridization to isolate genes that are highly expressed in normal intestinal mucosa but not expressed or expressed at a lower level in colon cancers (3), we obtained a clone that is identical to ST14. We further assigned the ST14 gene to human chromosome 11q24 (4). Takeuchi et al. also cloned ST14 from a human prostate cancer cell line and designated it the membrane type serine proteinase 1 (5). ST14 was detected in colon carcinomas, immortalized breast epithelial cell lines, breast cancer cell lines, and prostate cancer cell lines but not in cultured fibroblasts or fibrosarcoma cells (3, 6). The localization of ST14 to the cell membrane was demonstrated by surface biotinylation techniques (7). ST14 (suppression of tumorigenicityST14 is composed of an N-terminal transmembrane signal, a trypsinlike serine protease catalytic (SP) 2 domain, a SEA domain, two tandem repeats of the complement subcomponent C1r/s (CUB) domains, and four tandem repeats of the low density lipoprotein receptor (LDLR) class A domains (5, 8, 9). Friedrich et al. illustrated the crystal structures of the catalytic domain of ST14 and its complex with a bovine pancreatic trypsin inhibitor (8). Kunitz type serine protease inhibitors, such as hepatocyte growth factor activator inhibitor-1 (HAI-1) (5, 9) and aprotinin (10), strongly inhibit ST14 through binding to its catalytic domain. Besides t...

show abstract

“…co-localize on the cell membrane surface (27,39) also supports the possible interaction, since mature ST14 is secreted into human milk in a complexed form (9).…”

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Gst-st14 Domains As Bait To Capture Preymentioning

confidence: 99%

See 2 more Smart Citations

Protein Interaction Analysis of ST14 Domains and Their Point and Deletion Mutants

Ding

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Because TMEFF1 directly associates with Cripto in both Xenopus and in mammalian cell culture, it is possible that TMEFF1 may directly participate in mediating Cripto signaling or modulate the nodal-independent signal transduction by Cripto in these cell contexts. Although these issues are currently under investigation, our studies reveal a key connection between TMEFF1 and Cripto function, and may provide important clues to our understanding of molecular mechanisms underlying a variety of activities mediated by Cripto and/or TMEFF family members, including influencing neuronal cell function and the formation and progression of cancers (Bianco et al 1999(Bianco et al , 2002(Bianco et al , 2003Horie et al 2000;Glynne-Jones et al 2001;Gery et al 2002Gery et al , 2003Siegel et al 2002).…”

Section: Genes and Development 2627mentioning

confidence: 99%

Tomoregulin-1 (TMEFF1) inhibits nodal signaling through direct binding to the nodal coreceptor Cripto

Harms¹,

Chang²

2003

Genes Dev.

View full text Add to dashboard Cite

Transforming growth factor ␤ (TGF-␤) signals regulate multiple processes during development and in adult. We recently showed that tomoregulin-1 (TMEFF1), a transmembrane protein, selectively inhibits nodal but not activin in early Xenopus embryos. Here we report that TMEFF1 binds to the nodal coreceptor Cripto, but does not associate with either nodal or the type I ALK (activin receptor-like kinase) 4 receptor in coimmunoprecipitation assays. The inhibition of the nodal signaling by TMEFF1 in Xenopus ectodermal explants is rescued with wild-type but not mutant forms of Cripto. Furthermore, we show that the Cripto-FRL1-Cryptic (CFC) domain in Cripto, which is essential for its binding to ALK4, is also important for its interaction with TMEFF1. Our results demonstrate for the first time that nodal signaling can be regulated by a novel mechanism of blocking the Cripto coreceptor.Supplemental material is available at http://www.genesdev.org. Members of the transforming growth factor ␤ (TGF-␤) family play pivotal roles in both invertebrate and vertebrate embryogenesis (for reviews, see Harland and Gerhart 1997;Schier and Shen 1999;Whitman 2001). During early vertebrate development, the activin/nodal/Vg1/ GDF1 subfamily of ligands is involved in induction and patterning of the mesodermal and endodermal germ layers. Subsequently, these ligands participate in regulation of left-right axis formation. Removal of gene functions in the activin/nodal/Vg1/GDF1 pathways by mutations, gene knockout, or dominant negative components leads to aberrant development of vertebrate embryos that are defective in mesendodermal tissues and have left-right laterality defect (Harland and Gerhart 1997;Schier and Shen 1999;Whitman 2001).Like other TGF-␤ ligands, activin/nodal/Vg1/GDF1 signals through two types of transmembrane serine/ threonine kinase receptors. On ligand binding, the constitutively active type II receptor forms a complex with the type I receptor ALK (activin receptor-like kinase) 4 and 7, and activates the type I receptor through phosphorylation. The activated ALK then phosphorylates the cytoplasmic signal transducers Smad2 and Smad3, which form a hexameric complex with the common Smad, Smad4, and translocate into the nucleus to regulate gene expression in conjunction with other transcription factors (for reviews, see Massague 1998; Shi and Massague 2003). All of these ligands use the same type I receptor ALK4 and the type II receptors ActRIIA/IIB; however, nodal and Vg1/GDF1, but not activin, also require a membrane-associated EGF-CFC protein belonging to the Cripto family as a coreceptor in their signaling transduction (Gritsman et al. 1999;Reissmann et al. 2001;Yeo and Whitman 2001;Bianco et al. 2002;Yan et al. 2002;Cheng et al. 2003). Mutation in the Cripto family member One-eyed pinhead (Oep) in zebrafish leads to defective nodal/Vg1/GDF1 signaling, so that the resulting embryos mimic those with the mutations in the nodal ligands (Gritsman et al. 1999;Cheng et al. 2003). In mouse, nodal mutants display several defects i...

show abstract

High-Dose TGF-β1 Impairs Mesenchymal Stem Cell–Mediated Bone Regeneration via Bmp2 Inhibition

Liu

Gan

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Transforming growth factor‐β1 (TGF‐β1) is a key factor in bone reconstruction. However, its pathophysiological role in non‐union and bone repair remains unclear. Here we demonstrated that TGF‐β1 was highly expressed in both C57BL/6 mice where new bone formation was impaired after autologous bone marrow mesenchymal stem cell (BMMSC) implantation in non‐union patients. High doses of TGF‐β1 inhibited BMMSC osteogenesis and attenuated bone regeneration in vivo. Furthermore, different TGF‐β1 levels exhibited opposite effects on osteogenic differentiation and bone healing. Mechanistically, low TGF‐β1 doses activated smad3, promoted their binding to bone morphogenetic protein 2 (Bmp2) promoter, and upregulated Bmp2 expression in BMMSCs. By contrast, Bmp2 transcription was inhibited by changing smad3 binding sites on its promoter at high TGF‐β1 levels. In addition, high TGF‐β1 doses increased tomoregulin‐1 (Tmeff1) levels, resulting in the repression of Bmp2 and bone formation in mice. Treatment with the TGF‐β1 inhibitor SB431542 significantly rescued BMMSC osteogenesis and accelerated bone regeneration. Our study suggests that high‐dose TGF‐β1 dampens BMMSC‐mediated bone regeneration by activating canonical TGF‐β/smad3 signaling and inhibiting Bmp2 via direct and indirect mechanisms. These data collectively show a previously unrecognized mechanism of TGF‐β1 in bone repair, and TGF‐β1 is an effective therapeutic target for treating bone regeneration disability. © 2019 American Society for Bone and Mineral Research.

show abstract

TMEFF1 and brain tumors

Cited by 23 publications

References 11 publications

Protein Interaction Analysis of ST14 Domains and Their Point and Deletion Mutants

Protein Interaction Analysis of ST14 Domains and Their Point and Deletion Mutants

Tomoregulin-1 (TMEFF1) inhibits nodal signaling through direct binding to the nodal coreceptor Cripto

High-Dose TGF-β1 Impairs Mesenchymal Stem Cell–Mediated Bone Regeneration via Bmp2 Inhibition

Contact Info

Product

Resources

About