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Binding Properties of the Transforming Growth Factor-? Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling.

ABSTRACT: Transforming growth factor (TGF) ?1, ?2, and ?3 (TGF-?1-TGF-?3, respectively) are small secreted signaling proteins that each signal through the TGF-? type I and type II receptors (T?RI and T?RII, respectively). However, TGF-?2, which is well-known to bind T?RII several hundred-fold more weakly than TGF-?1 and TGF-?3, has an additional requirement for betaglycan, a membrane-anchored nonsignaling receptor. Betaglycan has two domains that bind TGF-?2 at independent sites, but how it binds TGF-?2 to potentiate T?RII binding and how the complex with TGF-?, T?RII, and betaglycan undergoes the transition to the signaling complex with TGF-?, T?RII, and T?RI are not understood. To investigate the mechanism, the binding of the TGF-?s to the betaglycan extracellular domain, as well as its two independent binding domains, either directly or in combination with the T?RI and T?RII ectodomains, was studied using surface plasmon resonance, isothermal titration calorimetry, and size-exclusion chromatography. These studies show that betaglycan binds TGF-? homodimers with a 1:1 stoichiometry in a manner that allows one molecule of T?RII to bind. These studies further show that betaglycan modestly potentiates the binding of T?RII and must be displaced to allow T?RI to bind. These findings suggest that betaglycan functions to bind and concentrate TGF-?2 on the cell surface and thus promote the binding of T?RII by both membrane-localization effects and allostery. These studies further suggest that the transition to the signaling complex is mediated by the recruitment of T?RI, which simultaneously displaces betaglycan and stabilizes the bound T?RII by direct receptor-receptor contact.

SUBMITTER: Villarreal MM

PROVIDER: S-EPMC5551644 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Binding Properties of the Transforming Growth Factor-β Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling.

Villarreal Maria M MM Kim Sun Kyung SK Barron Lindsey L Kodali Ravi R Baardsnes Jason J Hinck Cynthia S CS Krzysiak Troy C TC Henen Morkos A MA Pakhomova Olga O Mendoza Valentín V O'Connor-McCourt Maureen D MD Lafer Eileen M EM López-Casillas Fernando F Hinck Andrew P AP

Biochemistry 20161202 49

Transforming growth factor (TGF) β1, β2, and β3 (TGF-β1-TGF-β3, respectively) are small secreted signaling proteins that each signal through the TGF-β type I and type II receptors (TβRI and TβRII, respectively). However, TGF-β2, which is well-known to bind TβRII several hundred-fold more weakly than TGF-β1 and TGF-β3, has an additional requirement for betaglycan, a membrane-anchored nonsignaling receptor. Betaglycan has two domains that bind TGF-β2 at independent sites, but how it binds TGF-β2 t ...[more]

PMID: 27951653

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Project description:?-Catenin-dependent Wnt signaling is initiated as Wnt binds to both the receptor FZD and coreceptor LRP5/6, which then assembles a multimeric complex at the cytoplasmic membrane face to recruit and inactivate the kinase GSK3. The large number and sequence diversity of Wnt isoforms suggest the possibility of domain-specific ligand-coreceptor interactions, and distinct binding sites on LRP6 for Wnt3a and Wnt9b have recently been identified in vitro. Whether mechanistically different interactions between Wnts and coreceptors might mediate signaling remains to be determined. It is also not clear whether coreceptor homodimerization induced extracellularly can activate Wnt signaling, as is the case for receptor tyrosine kinases. We generated monoclonal antibodies against LRP6 with the unexpected ability to inhibit signaling by some Wnt isoforms and potentiate signaling by other isoforms. In cell culture, two antibodies characterized further show reciprocal activities on most Wnts, with one antibody antagonizing and the other potentiating. We demonstrate that these antibodies bind to different regions of LRP6 protein, and inhibition of signaling results from blocking Wnt binding. Antibody-mediated dimerization of LRP6 can potentiate signaling only when a Wnt isoform is also able to bind the complex, presumably recruiting FZD. Endogenous autocrine Wnt signaling in different tumor cell lines can be either antagonized or enhanced by the LRP6 antibodies, indicating expression of different Wnt isoforms. As anticipated from the roles of Wnt signaling in cancer and bone development, antibody activities can also be observed in mice for inhibition of tumor growth and in organ culture for enhancement of bone mineral density. Collectively, our results indicate that separate binding sites for different subsets of Wnt isoforms determine the inhibition or potentiation of signaling conferred by LRP6 antibodies. This complexity of coreceptor-ligand interactions may allow for differential regulation of signaling by Wnt isoforms during development, and can be exploited with antibodies to differentially manipulate Wnt signaling in specific tissues or disease states.

Dataset Information

Binding Properties of the Transforming Growth Factor-? Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling.

Publications

Binding Properties of the Transforming Growth Factor-β Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling.

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