Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling.

TitleAntibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling.
Publication TypeJournal Article
Year of Publication2014
AuthorsKumar S, Pan CC, Bloodworth JC, Nixon AB, Theuer C, Hoyt DG, Lee NY
Date Published2014 Jul 24
KeywordsAngiogenesis Inhibitors, Animals, Antibodies, Monoclonal, Antigens, CD, Cell Membrane, Cell Movement, Cercopithecus aethiops, COS Cells, Drug Screening Assays, Antitumor, Endoglin, Human Umbilical Vein Endothelial Cells, Humans, Matrix Metalloproteinase 14, Neovascularization, Pathologic, Protein Transport, Proteolysis, Receptors, Cell Surface, Signal Transduction, Smad Proteins, Transforming Growth Factor beta

Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell-cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis.

Alternate JournalOncogene
PubMed ID24077288
PubMed Central IDPMC3969897
Grant ListP30 CA014236 / CA / NCI NIH HHS / United States
R00 HL103791 / HL / NHLBI NIH HHS / United States
R01 CA178443 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
Nam Lee, Ph.D.