Academic Appointments

  • Basic Life Research Scientist, Biology

Honors & Awards

  • HHMI Hanna H. Gray Fellow, Howard Hughes Medical Institute (2019-present)
  • Damon Runyon Postdoctoral Fellowship, Damon Runyon Cancer Research Foundation (2018-2019)

Professional Education

  • B.A., Northwestern University, Biological Sciences (2010)

All Publications

  • Two intrinsic timing mechanisms set start and end times for dendritic arborization of a nociceptive neuron. Proceedings of the National Academy of Sciences of the United States of America Suzuki, N., Zou, Y., Sun, H., Eichel, K., Shao, M., Shih, M., Shen, K., Chang, C. 2022; 119 (45): e2210053119


    Choreographic dendritic arborization takes place within a defined time frame, but the timing mechanism is currently not known. Here, we report that the precisely timed lin-4-lin-14 regulatory circuit triggers an initial dendritic growth activity, whereas the precisely timed lin-28-let-7-lin-41 regulatory circuit signals a subsequent developmental decline in dendritic growth ability, hence restricting dendritic arborization within a set time frame. Loss-of-function mutations in the lin-4 microRNA gene cause limited dendritic outgrowth, whereas loss-of-function mutations in its direct target, the lin-14 transcription factor gene, cause precocious and excessive outgrowth. In contrast, loss-of-function mutations in the let-7 microRNA gene prevent a developmental decline in dendritic growth ability, whereas loss-of-function mutations in its direct target, the lin-41 tripartite motif protein gene, cause further decline. lin-4 and let-7 regulatory circuits are expressed in the right place at the right time to set start and end times for dendritic arborization. Replacing the lin-4 upstream cis-regulatory sequence at the lin-4 locus with a late-onset let-7 upstream cis-regulatory sequence delays dendrite arborization, whereas replacing the let-7 upstream cis-regulatory sequence at the let-7 locus with an early-onset lin-4 upstream cis-regulatory sequence causes a precocious decline in dendritic growth ability. Our results indicate that the lin-4-lin-14 and the lin-28-let-7-lin-41 regulatory circuits control the timing of dendrite arborization through antagonistic regulation of the DMA-1 receptor level on dendrites. The LIN-14 transcription factor likely directly represses dma-1 gene expression through a transcriptional means, whereas the LIN-41 tripartite motif protein likely indirectly promotes dma-1 gene expression through a posttranscriptional means.

    View details for DOI 10.1073/pnas.2210053119

    View details for PubMedID 36322763

  • Endocytosis in the axon initial segment maintains neuronal polarity. Nature Eichel, K., Uenaka, T., Belapurkar, V., Lu, R., Cheng, S., Pak, J. S., Taylor, C. A., Sudhof, T. C., Malenka, R., Wernig, M., Ozkan, E., Perrais, D., Shen, K. 2022


    Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly1. The axon initial segment (AIS) is a specialized domain that separates a neuron's morphologically, biochemically and functionally distinct axon and dendrite compartments2,3. How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism thatis likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries.

    View details for DOI 10.1038/s41586-022-05074-5

    View details for PubMedID 35978188

  • The function of the axon initial segment in neuronal polarity. Developmental biology Eichel, K., Shen, K. 2022


    Neurons are highly polarized cells with extensive axonal and dendritic projections that send and receive signals over long distances. Neuronal polarity requires sorting and maintaining a unique set of proteins to the neuron's distinct axonal and somatodendritic domains. The axon initial segment (AIS) is a specialized subcellular region located between the two domains and is critical for neuronal polarity. The AIS has a complex and elaborately organized molecular structure that enables its functions in neuronal polarity. Disruption of the AIS is associated with neurodevelopmental and neuropsychiatric disease pathologies, thus highlighting the importance of the AIS in neuronal physiology. This review discusses recent progress toward understanding the molecular architecture of the AIS and its importance in neuronal polarity through regulating protein diffusion and vesicular trafficking.

    View details for DOI 10.1016/j.ydbio.2022.05.016

    View details for PubMedID 35640681

  • Catalytic activation of beta-arrestin by GPCRs NATURE Eichel, K., Jullie, D., Barsi-Rhyne, B., Latorraca, N. R., Masureel, M., Sibarita, J., Dror, R. O., von Zastrow, M. 2018; 557 (7705): 381-+


    β-arrestins are critical regulator and transducer proteins for G-protein-coupled receptors (GPCRs). β-arrestin is widely believed to be activated by forming a stable and stoichiometric GPCR-β-arrestin scaffold complex, which requires and is driven by the phosphorylated tail of the GPCR. Here we demonstrate a distinct and additional mechanism of β-arrestin activation that does not require stable GPCR-β-arrestin scaffolding or the GPCR tail. Instead, it occurs through transient engagement of the GPCR core, which destabilizes a conserved inter-domain charge network in β-arrestin. This promotes capture of β-arrestin at the plasma membrane and its accumulation in clathrin-coated endocytic structures (CCSs) after dissociation from the GPCR, requiring a series of interactions with membrane phosphoinositides and CCS-lattice proteins. β-arrestin clustering in CCSs in the absence of the upstream activating GPCR is associated with a β-arrestin-dependent component of the cellular ERK (extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular β-arrestin function that is activated catalytically by GPCRs.

    View details for PubMedID 29720660

  • Phosphorylated EGFR Dimers Are Not Sufficient to Activate Ras. Cell reports Liang, S. I., van Lengerich, B., Eichel, K., Cha, M., Patterson, D. M., Yoon, T. Y., von Zastrow, M., Jura, N., Gartner, Z. J. 2018; 22 (10): 2593-2600


    Growth factor binding to EGFR drives conformational changes that promote homodimerization and transphosphorylation, followed by adaptor recruitment, oligomerization, and signaling through Ras. Whether specific receptor conformations and oligomerization states are necessary for efficient activation of Ras is unclear. We therefore evaluated the sufficiency of a phosphorylated EGFR dimer to activate Ras without growth factor by developing a chemical-genetic strategy to crosslink and "trap" full-length EGFR homodimers on cells. Trapped dimers become phosphorylated and recruit adaptor proteins at stoichiometry equivalent to that of EGF-stimulated receptors. Surprisingly, these phosphorylated dimers do not activate Ras, Erk, or Akt. In the absence of EGF, phosphorylated dimers do not further oligomerize or reorganize on cell membranes. These results suggest that a phosphorylated EGFR dimer loaded with core signaling adapters is not sufficient to activate Ras and that EGFR ligands contribute to conformational changes or receptor dynamics necessary for oligomerization and efficient signal propagation through the SOS-Ras-MAPK pathway.

    View details for DOI 10.1016/j.celrep.2018.02.031

    View details for PubMedID 29514089

    View details for PubMedCentralID PMC5916813

  • Subcellular Organization of GPCR Signaling. Trends in pharmacological sciences Eichel, K., von Zastrow, M. 2018; 39 (2): 200-208


    G protein-coupled receptors (GPCRs) comprise a large and diverse class of signal-transducing receptors that undergo dynamic and isoform-specific membrane trafficking. GPCRs thus have an inherent potential to initiate or regulate signaling reactions from multiple membrane locations. This review discusses emerging insights into the subcellular organization of GPCR function in mammalian cells, focusing on signaling transduced by heterotrimeric G proteins and β-arrestins. We summarize recent evidence indicating that GPCR-mediated activation of G proteins occurs not only from the plasma membrane (PM) but also from endosomes and Golgi membranes and that β-arrestin-dependent signaling can be transduced from the PM by β-arrestin trafficking to clathrin-coated pits (CCPs) after dissociation from a ligand-activated GPCR.

    View details for DOI 10.1016/

    View details for PubMedID 29478570

    View details for PubMedCentralID PMC5830169

  • Genetic evidence that β-arrestins are dispensable for the initiation of β2-adrenergic receptor signaling to ERK. Science signaling O'Hayre, M., Eichel, K., Avino, S., Zhao, X., Steffen, D. J., Feng, X., Kawakami, K., Aoki, J., Messer, K., Sunahara, R., Inoue, A., von Zastrow, M., Gutkind, J. S. 2017; 10 (484)


    The β2-adrenergic receptor (β2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β2AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β2AR internalization. Unexpectedly, β-arr1 and β-arr2 and receptor internalization were dispensable for ERK activation. Instead, β2AR signaled through Gαs and Gβγ subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for β2AR signaling through β-arrestin-independent pathways in key physiological functions and under pathological conditions.

    View details for DOI 10.1126/scisignal.aal3395

    View details for PubMedID 28634209

    View details for PubMedCentralID PMC5751434

  • An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells CELL Lobingier, B. T., Huttenhain, R., Eichel, K., Miller, K. B., Ting, A. Y., von Zastrow, M., Krogan, N. J. 2017; 169 (2): 350-360


    Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial resolution necessary to interrogate specific protein networks. We provide a solution to this problem by combining quantitative proteomics with a system of spatial references. As proof of principle, we apply this approach to interrogate proteins engaged by G-protein-coupled receptors as they dynamically signal and traffic in response to ligand-induced activation. The method resolves known binding partners, as well as previously unidentified network components. Validating its utility as a discovery pipeline, we establish that two of these proteins promote ubiquitin-linked receptor downregulation after prolonged activation.

    View details for DOI 10.1016/j.cell.2017.03.022

    View details for Web of Science ID 000398349500018

    View details for PubMedID 28388416

  • beta-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation NATURE CELL BIOLOGY Eichel, K., Jullie, D., von Zastrow, M. 2016; 18 (3): 303-?


    β-Arrestins critically regulate G-protein-coupled receptor (GPCR) signalling, not only 'arresting' the G protein signal but also modulating endocytosis and initiating a discrete G-protein-independent signal through MAP kinase. Despite enormous recent progress towards understanding biophysical aspects of arrestin function, arrestin cell biology remains relatively poorly understood. Two key tenets underlie the prevailing current view: β-arrestin accumulates in clathrin-coated structures (CCSs) exclusively in physical complex with its activating GPCR, and MAP kinase activation requires endocytosis of formed GPCR-β-arrestin complexes. We show here, using β1-adrenergic receptors, that β-arrestin-2 (arrestin 3) accumulates robustly in CCSs after dissociating from its activating GPCR and transduces the MAP kinase signal from CCSs. Moreover, inhibiting subsequent endocytosis of CCSs enhances the clathrin- and β-arrestin-dependent MAP kinase signal. These results demonstrate β-arrestin 'activation at a distance', after dissociating from its activating GPCR, and signalling from CCSs. We propose a β-arrestin signalling cycle that is catalytically activated by the GPCR and energetically coupled to the endocytic machinery.

    View details for DOI 10.1038/ncb3307

    View details for Web of Science ID 000371031300011

    View details for PubMedID 26829388

    View details for PubMedCentralID PMC4767649

  • Functional Conservation of Cis-Regulatory Elements of Heat-Shock Genes over Long Evolutionary Distances PLOS ONE He, Z., Eichel, K., Ruvinsky, I. 2011; 6 (7)


    Transcriptional control of gene regulation is an intricate process that requires precise orchestration of a number of molecular components. Studying its evolution can serve as a useful model for understanding how complex molecular machines evolve. One way to investigate evolution of transcriptional regulation is to test the functions of cis-elements from one species in a distant relative. Previous results suggested that few, if any, tissue-specific promoters from Drosophila are faithfully expressed in C. elegans. Here we show that, in contrast, promoters of fly and human heat-shock genes are upregulated in C. elegans upon exposure to heat. Inducibility under conditions of heat shock may represent a relatively simple "on-off" response, whereas complex expression patterns require integration of multiple signals. Our results suggest that simpler aspects of regulatory logic may be retained over longer periods of evolutionary time, while more complex ones may be diverging more rapidly.

    View details for DOI 10.1371/journal.pone.0022677

    View details for Web of Science ID 000293172900066

    View details for PubMedID 21799932

    View details for PubMedCentralID PMC3143172