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1. Mechanisms for Regulating and Organizing Receptor Signaling by Endocytosis

   https://doi.org/10.1146/annurev-biochem-081820-092427  

   von Zastrow, Mark; Sorkin, Alexander (June 2021, Annual Review of Biochemistry)

   null (Ed.)

   Intricate relationships between endocytosis and cellular signaling, first recognized nearly 40 years ago through the study of tyrosine kinase growth factor receptors, are now known to exist for multiple receptor classes and to affect myriad physiological and developmental processes. This review summarizes our present understanding of how endocytosis orchestrates cellular signaling networks, with an emphasis on mechanistic underpinnings and focusing on two receptor classes—tyrosine kinase and G protein–coupled receptors—that have been investigated in particular detail. Together, these examples provide a useful survey of the current consensus, uncertainties, and controversies in this rapidly advancing area of cell biology. 

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2. 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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3. WASP family proteins regulate the mobility of the B cell receptor during signaling activation

   https://doi.org/10.1038/s41467-020-14335-8  

   Rey-Suarez, Ivan; Wheatley, Brittany A.; Koo, Peter; Bhanja, Anshuman; Shu, Zhou; Mochrie, Simon; Song, Wenxia; Shroff, Hari; Upadhyaya, Arpita (January 2020, Nature Communications)

   Abstract Regulation of membrane receptor mobility tunes cellular response to external signals, such as in binding of B cell receptors (BCR) to antigen, which initiates signaling. However, whether BCR signaling is regulated by BCR mobility, and what factors mediate this regulation, are not well understood. Here we use single molecule imaging to examine BCR movement during signaling activation and a novel machine learning method to classify BCR trajectories into distinct diffusive states. Inhibition of actin dynamics downstream of the actin nucleating factors, Arp2/3 and formin, decreases BCR mobility. Constitutive loss or acute inhibition of the Arp2/3 regulator, N-WASP, which is associated with enhanced signaling, increases the proportion of BCR trajectories with lower diffusivity. Furthermore, loss of N-WASP reduces the diffusivity of CD19, a stimulatory co-receptor, but not that of FcγRIIB, an inhibitory co-receptor. Our results implicate a dynamic actin network in fine-tuning receptor mobility and receptor-ligand interactions for modulating B cell signaling. 

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4. Regulation of AMPA receptor trafficking by secreted protein factors

   https://doi.org/10.3389/fncel.2023.1271169  

   Rennich, Bethany J.; Luth, Eric S.; Moores, Samantha; Juo, Peter (November 2023, Frontiers in Cellular Neuroscience)

   AMPA receptors (AMPARs) mediate the majority of fast excitatory transmission in the brain. Regulation of AMPAR levels at synapses controls synaptic strength and underlies information storage and processing. Many proteins interact with the intracellular domain of AMPARs to regulate their trafficking and synaptic clustering. However, a growing number of extracellular factors important for glutamatergic synapse development, maturation and function have emerged that can also regulate synaptic AMPAR levels. This mini-review highlights extracellular protein factors that regulate AMPAR trafficking to control synapse development and plasticity. Some of these factors regulate AMPAR clustering and mobility by interacting with the extracellular N-terminal domain of AMPARs whereas others regulate AMPAR trafficking indirectly via their respective signaling receptors. While several of these factors are secreted from neurons, others are released from non-neuronal cells such as glia and muscle. Although it is apparent that secreted factors can act locally on neurons near their sites of release to coordinate individual synapses, it is less clear if they can diffuse over longer ranges to coordinate related synapses within a circuit or region of the brain. Given that there are hundreds of factors that can be secreted from neuronal and non-neuronal cells, it will not be surprising if more extracellular factors that modulate AMPARs and glutamatergic synapses are discovered. Many open questions remain including where and when the factors are expressed, what regulates their secretion from different cell types, what controls their diffusion, stability, and range of action, and how their cognate receptors influence intracellular signaling to control AMPAR trafficking. 

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5. Click-to-lead design of a picomolar ABA receptor antagonist with potent activity in vivo

   https://doi.org/10.1073/pnas.2108281118  

   Vaidya, Aditya S; Peterson, Francis C; Eckhardt, James; Xing, Zenan; Park, Sang-Youl; Dejonghe, Wim; Takeuchi, Jun; Pri-Tal, Oded; Faria, Julianna; Elzinga, Dezi; et al (September 2021, Proceedings of the National Academy of Sciences)

   Significance Abscisic acid (ABA) is a phytohormone that plants utilize to coordinate responses to abiotic stress, modulate seed dormancy, and is central to plant development in several contexts. Chemicals that activate or block ABA signaling are useful as research tools and as potential agrochemical leads. Many successes have been reported for ABA activators (agonists), but existing ABA blockers (antagonists) are limited by modest in vivo activity. Here we report antabactin (ANT), a potent ABA blocker developed using “click chemistry”–based diversification of a known ABA activator. Structural studies reveal, ANT disrupts signaling by stabilizing ABA receptors in an unproductive form. ANT can accelerate seed germination in multiple species, making it a chemical tool for improving germination. 

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