Our research
Our cells function like miniature computers
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Our cells constantly sense inputs from the environment through receptors on the cell surface. The receptors translate these inputs into intracellular signals, which are then processed through intricate and dynamic networks of proteins to generate cellular responses. G protein-coupled receptors (GPCRs) represent the largest signaling receptor family with over 800 members in humans and can detect a wide range of inputs, including hormones, neurotransmitters, odors, and light.
Given their fundamental role in health and disease, GPCRs are prime targets for drug development — about one-third of current medications target them. However, our current understanding of intracellular responses to GPCR activation primarily focuses on a small set of proteins. This limited understanding fails to fully explain the remarkable specificity of GPCR signaling, suggesting the existence of additional layers of specialization in GPCR signaling at the cellular level that remain unexplored.
The Huttenhain Lab deciphers how GPCRs decode extracellular cues into dynamic and context-specific cellular signaling networks to elicit diverse physiologic responses. We exploit quantitative proteomics to capture the spatiotemporal organization of signaling networks combined with functional genomics to study their impact on cell biology and physiology.
A versatile omics toolbox to resolve signaling networks with temporal and spatial resolution
To characterize protein interaction networks, we developed a proximity biotin labeling method using engineered peroxidase, APEX, combined with quantitative proteomics. This technique captures snapshots of proximal proteomes in living cells with sub-minute temporal and sub-cellular spatial resolution. Applied to GPCRs, GPCR-APEX reveals proximal protein interactions and receptor location by quantifying proteins biotinylated near the activated receptor.
Building on the impact of GPCR-APEX in characterizing responses to GPCR activation, we continue to develop technologies integrating proteomics and functional genomics to comprehensively capture cellular responses to receptor activation.
A multidimensional screening platform to develop unprecedented types of drugs
Traditionally, GPCR-targeting drugs are classified as agonists, which activate receptors, or antagonists, which block them. However, recent research reveals more complexity in how these drugs modulate receptor activity. GPCRs can activate multiple signaling pathways and signal from internal cellular compartments, offering new pharmacological opportunities. This has sparked interest in designing drugs that tailor GPCR activity to specific states, locations, and pathways.
The Huttenhain Lab is developing a platform for multidimensional characterization of GPCR ligands using proteomic technologies in human iPSC-derived systems. This platform aims to classify ligands with novel pharmacology and identify molecular determinants of GPCR signaling, enabling unprecedented modulation of these pathways.
Exploring novel molecular mechanisms in GPCR signaling and trafficking
Our lab is interested in uncovering molecular determinants that define the signaling specificity of GPCRs. By integrating unbiased proteomic data across diverse receptors or distinct ligands targeting the same receptor, we strive to identify key regulatory nodes within the signaling networks. To validate the roles of these nodes in GPCR signaling, we combine functional genomics with targeted assays for receptor signaling and trafficking, including biosensors, transcriptional reporter, and fluorescent imaging.
