About

Xin-Yun Huang, Ph.D., is a Professor of Biochemistry and Biophysics at Weill Cornell Medicine. His laboratory focuses on deciphering the structural biochemistry of membrane-spanning signaling proteins, particularly seven-transmembrane GPCRs and single-pass receptors, to reveal the molecular logic of cross-membrane communication. His research also involves engineering small-molecule fascin inhibitors that can arrest tumor metastasis and invigorate intratumoral dendritic cells, opening new frontiers in precision cancer therapy.

Research topics

• Endocrinology
• Cell biology
• Biophysics
• Biochemistry
• Biology

Selected publications

• Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor

  Molecular Cell · 2020 · 87 citations

  Senior authorCorresponding
  • Biology
  • Cell biology
  • Biophysics
  PublisherOA PDFDOI

• Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

  Journal of Molecular Biology · 2018-03-21 · 53 citations

  articleOpen accessSenior authorCorresponding

  Tumor metastasis is responsible for ~ 90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main actin-bundling protein in filopodia. Small-molecule fascin inhibitors block tumor cell migration, invasion, and metastasis. Here we present the structural basis for the mechanism of action of these small-molecule fascin inhibitors. X-ray crystal structural analysis of a complex of fascin and a fascin inhibitor shows that binding of the fascin inhibitor to the hydrophobic cleft between the domains 1 and 2 of fascin induces a ~ 35o rotation of domain 1, leading to the distortion of both the actin-binding sites 1 and 2 on fascin. Furthermore, the crystal structures of an inhibitor alone indicate that the conformations of the small-molecule inhibitors are dynamic. Mutations of the inhibitor-interacting residues decrease the sensitivity of fascin to the inhibitors. Our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.

  PublisherDOI

• Regulation, Signaling, and Physiological Functions of G-Proteins

  Journal of Molecular Biology · 2016-08-08 · 492 citations

  reviewOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Critical Roles of STAT3 in β-Adrenergic Functions in the Heart

  Circulation · 2015-12-02 · 64 citations

  article

  BACKGROUND: β-Adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. METHODS AND RESULTS: We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β1AR, protein kinase A, and T-type Ca(2+) channels. CONCLUSIONS: Our data demonstrate for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodeling, and heart failure.

  PublisherDOI

• Pivotal Role of Extended Linker 2 in the Activation of Gα by G Protein-coupled Receptor

  Journal of Biological Chemistry · 2014-11-21 · 10 citations

  articleOpen accessSenior author

  G protein-coupled receptors (GPCRs) relay extracellular signals mainly to heterotrimeric G-proteins (Gαβγ) and they are the most successful drug targets. The mechanisms of G-protein activation by GPCRs are not well understood. Previous studies have revealed a signal relay route from a GPCR via the C-terminal α5-helix of Gα to the guanine nucleotide-binding pocket. Recent structural and biophysical studies uncover a role for the opening or rotating of the α-helical domain of Gα during the activation of Gα by a GPCR. Here we show that β-adrenergic receptors activate eight Gαs mutant proteins (from a screen of 66 Gαs mutants) that are unable to bind Gβγ subunits in cells. Five of these eight mutants are in the αF/Linker 2/β2 hinge region (extended Linker 2) that connects the Ras-like GTPase domain and the α-helical domain of Gαs. This extended Linker 2 is the target site of a natural product inhibitor of Gq. Our data show that the extended Linker 2 is critical for Gα activation by GPCRs. We propose that a GPCR via its intracellular loop 2 directly interacts with the β2/β3 loop of Gα to communicate to Linker 2, resulting in the opening and closing of the α-helical domain and the release of GDP during G-protein activation.

  PublisherOA PDFDOI

• Mouse Models for Tumor Metastasis

  Methods in molecular biology · 2012-01-01 · 117 citations

  articleSenior author

  Tumor metastasis is the main cause of death of cancer patients. Here we describe two mouse models for investigating tumor metastasis. In the first spontaneous metastasis mouse model, 4T1 mouse breast tumor cells are injected into the mammary gland of host mice and the metastasis of 4T1 tumor cells into the lung are examined with a colonogenic assay. In the second experimental metastasis mouse model, luciferase-labeled MDA-MB-231 human breast tumor cells are injected into the tail vein of NOD-SCID immunodeficient mice and the colonization of MDA-MB-231 tumor cells in the lung are monitored using noninvasive bioluminescence imaging.

  PublisherDOI

• Molecular Mechanism of Fascin Function in Filopodial Formation

  Journal of Biological Chemistry · 2012-11-27 · 126 citations

  articleOpen accessSenior author

  Filopodia are cell surface protrusions that are essential for cell migration. This finger-like structure is supported by rigid tightly bundled actin filaments. The protein responsible for actin bundling in filopodia is fascin. However, the mechanism by which fascin functions in filopodial formation is not clear. Here we provide biochemical, cryo-electron tomographic, and x-ray crystal structural data demonstrating the unique structural characteristics of fascin. Systematic mutagenesis studies on 100 mutants of fascin indicate that there are two major actin-binding sites on fascin. Crystal structures of four fascin mutants reveal concerted conformational changes in fascin from inactive to active states in the process of actin bundling. Mutations in any one of the actin-binding sites impair the cellular function of fascin in filopodial formation. Altogether, our data reveal the molecular mechanism of fascin function in filopodial formation.

  PublisherDOI

• Resistance to Inhibitors of Cholinesterase-8A (Ric-8A) Is Critical for Growth Factor Receptor-induced Actin Cytoskeletal Reorganization

  Journal of Biological Chemistry · 2011-07-20 · 33 citations

  articleOpen accessSenior author

  Heterotrimeric G proteins are critical transducers of cellular signaling. In addition to their classic roles in relaying signals from G protein-coupled receptors (GPCRs), heterotrimeric G proteins also mediate physiological functions from non-GPCRs. Previously, we have shown that Gα(13), a member of the heterotrimeric G proteins, is essential for growth factor receptor-induced actin cytoskeletal reorganization such as dynamic dorsal ruffle turnover and cell migration. These Gα(13)-mediated dorsal ruffle turnover and cell migration by growth factors acting on their receptor tyrosine kinases (RTKs) are independent of GPCRs. However, the mechanism by which RTKs signal to Gα(13) is not known. Here, we show that cholinesterase-8A (Ric-8A), a nonreceptor guanine nucleotide exchange factor for some heterotrimeric G proteins, is critical for coupling RTKs to Gα(13). Down-regulation of Ric-8A protein levels in cells by RNA interference slowed down platelet-derived growth factor (PDGF)-induced dorsal ruffle turnover and inhibited PDGF-initiated cell migration. PDGF was able to increase the activity of Ric-8A in cells. Furthermore, purified Ric-8A proteins interact directly with purified Gα(13) protein in a nucleotide-dependent manner. Deficiency of Ric-8A prevented the translocation of Gα(13) to the cell cortex. Hence, Ric-8A is critical for growth factor receptor-induced actin cytoskeletal reorganization.

  PublisherOA PDFDOI

• Erratum: Migrastatin analogues target fascin to block tumour metastasis

  Nature · 2011-07-20 · 5 citations

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• Migrastatin analogues target fascin to block tumour metastasis

  Nature · 2010-04-13 · 263 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AG023202

  NIH · $2.0M · 2008

• NIH Grant R01HL091525

  NIH · $2.1M · 2014

• NIH Grant R01CA136837

  NIH · $1.0M · 2013

• Functions of G-proteins in Endothelial Cells

  NIH · $1.7M · 2016–2020

• Molecular Basis of B1-Adrenergic Receptor Function

  NIH · $1.5M · 2020–2025

Frequent coauthors

• J. Jillian Zhang

  Hangzhou Normal University

  72 shared

• M Snyder

  65 shared

• Wei Zhang

  China-Japan Friendship Hospital

  64 shared

• Weinian Shou

  64 shared

• Michael Rubart

  Indiana University School of Medicine

  64 shared

• Biyi Chen

  University of Iowa

  64 shared

• Meijing Wang

  Zhejiang Sci-Tech University

  64 shared

• Long‐Sheng Song

  University of Iowa

  64 shared