Research Summary:
Receptor tyrosine kinases, kinase regulatory mechanisms, membrane proteins, feedback regulation of cell signaling Summary: We study basic mechanisms of cellular signaling by Receptor Tyrosine Kinases with a goal to understand how cells receive and process growth signals provided by the neighboring cells and the extracellular milieu. Receptor Tyrosine Kinases are single pass transmembrane receptors that catalyze tyrosine phosphorylation upon activation of their intracellular kinase domains. These receptors are principal regulators of growth and survival signals in cells and therefore frequently become deregulated in human diseases. We are interested in understanding how the kinase activity of these receptors is regulated by ligand binding and how the receptors associate with their regulatory components during the activation process. By combining biochemistry and cell biology we are studying these processes in the reconstituted membrane systems in vitro and in the plasma membrane of the living cells. We also use crystallography to gain an atomic resolution insight into Receptor Tyrosine Kinase regulation that will help us design new approaches for therapeutic intervention.
Publications
Structures of the PI3Kα/KRas complex on lipid bilayers reveal the molecular mechanism of PI3Kα activation.
Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning.
G3BP isoforms differentially affect stress granule assembly and gene expression during cellular stress.
Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain.
Protein-protein interactions with G3BPs drive stress granule condensation and gene expression changes under cellular stress.
Structural dynamics of the active HER4 and HER2/HER4 complexes is finely tuned by different growth factors and glycosylation.
Hedgehog target genes regulate lipid metabolism to drive basal cell carcinoma and medulloblastoma.
Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3.
Trapping Tribbles: Nanobody-assisted structure of the TRIB2 pseudokinase.
Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling.
Structural basis for signaling by the HER3 pseudokinase receptor.
CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids.
An effective strategy for ligand-mediated pulldown of the HER2/HER3/NRG1β heterocomplex and cryo-EM structure determination at low sample concentrations.
Efficient expression, purification, and visualization by cryo-EM of unliganded near full-length HER3.
Author Correction: Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface.
Cryo-EM structures of the near full-length HER2/HER3 heterodimer reveal a novel allosteric mechanism of activation.
Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling.
Preface.
Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.
A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization.
Mutant HER2 needs mutant HER3 to be an effective oncogene.
Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant.
CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.
CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.
State of the structure address on MET receptor activation by HGF.
A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics.
Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.
Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2.
Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers.
Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking.
Expression and purification of active human kinases using Pichia pastoris as a general-purpose host.
Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
The structure of a calsequestrin filament reveals mechanisms of familial arrhythmia.
A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing.
Receptor tyrosine kinase activation: From the ligand perspective.
The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region.
PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization.
Prospects for pharmacological targeting of pseudokinases.
Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.
The pseudokinase TRIB1 toggles an intramolecular switch to regulate COP1 nuclear export.
Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation.
Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations.
Activating HER3 mutations in breast cancer.
Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23.
Feedback regulation of RTK signaling in development.
Switching on BTK-One Domain at a Time.
EGF and NRG induce phosphorylation of HER3/ERBB3 by EGFR using distinct oligomeric mechanisms.
Structural Basis for the Non-catalytic Functions of Protein Kinases.
Src defines a new pool of EGFR substrates.
Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor.
Structural Features of the Kinase Domain.
Science Signaling Podcast: 2 December 2014.
Structural analysis of the EGFR/HER3 heterodimer reveals the molecular basis for activating HER3 mutations.
A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties.
Regulation of the HER3/ErbB3 Pseudokinase Domain by an ATP-Competitive Inhibitor.
Single Molecule Imaging of Human Epidermal Growth Factor Receptors.
EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma.
EGFR lung cancer mutants get specialized.
Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms.
Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.
Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment.
Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment.
Mapping cellular routes of Ras: a ubiquitin trail.
A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen.
Differential modification of Ras proteins by ubiquitination.
An ex vivo model for functional studies of myofibroblasts.
Inactivation of membrane tumor necrosis factor alpha by gingipains from Porphyromonas gingivalis.
Tumour necrosis factor-alpha stimulates expression of TNF-alpha converting enzyme in endothelial cells.
Inactivation of Src family kinases inhibits angiogenesis in vivo: implications for a mechanism involving organization of the actin cytoskeleton.
hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl.
555 & 535 Mission Bay Blvd Sou, Rm 452W
UCSF Box 3122
San Francisco, CA 94158
United States