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1. Mapping Tyrosine Kinase Receptor Dimerization to Receptor Expression and Ligand Affinities

   https://doi.org/10.3390/pr7050288  

   Mamer, Spencer B. ; Palasz, Alexandra A. ; Imoukhuede, P. I. ( May 2019 , Processes)

   Tyrosine kinase receptor (RTK) ligation and dimerization is a key mechanism for translating external cell stimuli into internal signaling events. This process is critical to several key cell and physiological processes, such as in angiogenesis and embryogenesis, among others. While modulating RTK activation is a promising therapeutic target, RTK signaling axes have been shown to involve complicated interactions between ligands and receptors both within and across different protein families. In angiogenesis, for example, several signaling protein families, including vascular endothelial growth factors and platelet-derived growth factors, exhibit significant cross-family interactions that can influence pathway activation. Computational approaches can provide key insight to detangle these signaling pathways but have been limited by the sparse knowledge of these cross-family interactions. Here, we present a framework for studying known and potential non-canonical interactions. We constructed generalized models of RTK ligation and dimerization for systems of two, three and four receptor types and different degrees of cross-family ligation. Across each model, we developed parameter-space maps that fully determine relative pathway activation for any set of ligand-receptor binding constants, ligand concentrations and receptor concentrations. Therefore, our generalized models serve as a powerful reference tool for predicting not only known ligand: Receptor axes but also how unknown interactions could alter signaling dimerization patterns. Accordingly, it will drive the exploration of cross-family interactions and help guide therapeutic developments across processes like cancer and cardiovascular diseases, which depend on RTK-mediated signaling. 

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2. Regulatory feedback on receptor and non‐receptor synthesis for robust signaling

   https://doi.org/10.1002/dvdy.160  

   Lander, Arthur D. ; Nie, Qing ; Sanchez‐Tapia, Cynthia ; Simonyan, Aghavni ; Wan, Frederic Y. M. ( February 2020 , Developmental Dynamics)

   Elaborate regulatory feedback processes are thought to make biological development robust, that is, resistant to changes induced by genetic or environmental perturbations. How this might be done is still not completely understood. Previous numerical simulations on reaction‐diffusion models of Dpp gradients in Drosophila wing imaginal disc have showed that feedback (of the Hill function type) on (signaling) receptors and/or non‐(signaling) receptors are of limited effectiveness in promoting robustness. Spatial nonuniformity of the feedback processes has also been shown theoretically to lead to serious shape distortion and a principal cause for ineffectiveness. Through mathematical modeling and analysis, the present article shows that spatially uniform nonlocal feedback mechanisms typically modify gradient shape through a shape parameter (that does not change with location). This in turn enables us to uncover new multi‐feedback instrument for effective promotion of robust signaling gradients.

    

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3. The glucocorticoid receptor potentiates aldosterone-induced transcription by the mineralocorticoid receptor

   https://doi.org/10.1073/pnas.2413737121  

   Johnson, Thomas_A ; Fettweis, Gregory ; Wagh, Kaustubh ; Ceacero-Heras, Diego ; Krishnamurthy, Manan ; Sánchez_de_Medina, Fermín ; Martínez-Augustin, Olga ; Upadhyaya, Arpita ; Hager, Gordon_L ; Alvarez_de_la_Rosa, Diego ( November 2024 , Proceedings of the National Academy of Sciences)

   The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR coexpression on MR genome-wide transcriptional responses and chromatin binding upon activation by aldosterone and glucocorticoids, both physiological ligands of this receptor. Transcriptional responses of MR in the absence of GR result in fewer regulated genes. In contrast, coexpression of GR potentiates MR-mediated transcription, particularly in response to aldosterone, both in cell lines and in the more physiologically relevant model of mouse colon organoids. MR chromatin binding is altered by GR coexpression in a locus- and ligand-specific way. Single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that coexpression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids.

    

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4. Naturally Occurring Genetic Variants in the Oxytocin Receptor Alter Receptor Signaling Profiles

   https://doi.org/10.1021/acsptsci.1c00095  

   Malik, M ; Ward, MD. ; Fang, Y ; Porter, JR. ; Zimmerman, MI ; Koelblen, T ; Roh, M ; Frolova, AI ; Burris, TP ; Bowman, GR ; et al ( September 2021 , ACS pharmacology translational science)
5. Allostery in oligomeric receptor models

   https://doi.org/10.1093/imammb/dqz016  

   Conradi Smith, Gregory Douglas ( December 2019 , Mathematical Medicine and Biology: A Journal of the IMA)

   null (Ed.)

   Abstract We show how equilibrium binding curves of receptor homodimers can be expressed as rational polynomial functions of the equilibrium binding curves of the constituent monomers, without approximation and without assuming independence of receptor monomers. Using a distinguished spanning tree construction for reduced graph powers, the method properly accounts for thermodynamic constraints and allosteric interactions between receptor monomers (i.e. conformational coupling). The method is completely general; it begins with an arbitrary undirected graph representing the topology of a monomer state-transition diagram and ends with an algebraic expression for the equilibrium binding curve of a receptor oligomer composed of two or more identical and indistinguishable monomers. Several specific examples are analysed, including guanine nucleotide-binding protein-coupled receptor dimers and tetramers composed of multiple ‘ternary complex’ monomers. 

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