A5076175732- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Protein Kinase Regulation and GTPase Signaling
- Immune cells in cancer
- Melanoma and MAPK Pathways
- Cytokine Signaling Pathways and Interactions
- Monoclonal and Polyclonal Antibodies Research
- Phagocytosis and Immune Regulation
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- Chronic Lymphocytic Leukemia Research
- Signaling Pathways in Disease
- Mosquito-borne diseases and control
- Prostate Cancer Treatment and Research
- Immune Response and Inflammation
- Ubiquitin and proteasome pathways
- Receptor Mechanisms and Signaling
- Galectins and Cancer Biology
- Diabetes and associated disorders
- Virology and Viral Diseases
- Protein Degradation and Inhibitors
- Viral Infections and Vectors
- interferon and immune responses
- Conferences and Exhibitions Management
- Inflammation biomarkers and pathways
University of Minnesota
2015-2024
University of Minnesota Medical Center
2015-2024
University of Minnesota System
2024
Twin Cities Orthopedics
2022-2023
Masonic Cancer Center
2020-2021
University of California, San Francisco
2010-2015
Howard Hughes Medical Institute
2010-2011
City College of San Francisco
2011
University of California, Berkeley
2006-2009
QB3
2009
The Ras-specific guanine nucleotide-exchange factors Son of sevenless (Sos) and Ras nucleotide-releasing factor 1 (RasGRF1) transduce extracellular stimuli into activation by catalyzing the exchange Ras-bound GDP for GTP. A truncated form RasGRF1 containing only core catalytic Cdc25 domain is sufficient stimulating nucleotide exchange, whereas isolated Sos inactive. At a site distal to site, nucleotide-bound binds Sos, making contacts with exchanger motif (Rem) domain. This allosteric...
The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking dimerization and conformation, we built an allosteric model inhibitor-induced that resolves the contributions inhibitor binding to two active sites dimer, revealing key differences between I inhibitors. For coupling...
Clustering of receptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs) initiates the macrophage antimicrobial response. ITAM engage Src-family tyrosine kinases (SFKs) to initiate phagocytosis and activation. Macrophages also encounter nonpathogenic molecules that cluster weakly must tune their sensitivity avoid inappropriate responses. To investigate this response threshold, we compared signaling in presence absence receptor clustering using a small-molecule...
The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking dimerization and conformation, we built an allosteric model inhibitor-induced that resolves the contributions inhibitor binding to two active sites dimer, revealing key differences between I inhibitors. For coupling...
The activity of Src-family kinases (SFKs), which phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs), is a critical factor regulating myeloid-cell activation. We reported previously that the SFK LynA uniquely susceptible to rapid ubiquitin-mediated degradation in macrophages, functioning as rheostat signaling (Freedman et al., 2015). now report mechanism by preferentially targeted for and how cell specificity built into rheostat. Using genetic, biochemical, quantitative...
The response to the COVID-19 crisis across most research institutions mandated ceasing nonessential activities in order minimize spread of virus our communities. With minimal notice, experiments were terminated, cell lines frozen, mouse colonies culled, and trainees prevented from performing bench research. Still, despite interruption experimental productivity, shutdown has proven for many PIs that doing thinking science are not bound laboratory. Furthermore, shutdowns have solidified...
Abstract In this article we describe the use of pharmacological and genetic tools coupled with immunoblotting (Western blotting) targeted mass spectrometry to quantify immune signaling cell activation mediated by tyrosine kinases. Transfer ATP γ phosphate a protein residue activates cascades regulating differentiation, survival, effector functions all cells, unique roles in antigen receptor, polarization, other pathways. Defining substrates scaffolding interactions kinases is critical for...
Abstract The kinase Csk is the primary negative regulator of Src-family kinases (SFKs, e.g., Lck, Fyn, Lyn, Hck, Fgr, Blk, Yes), phosphorylating a tyrosine on SFK C-terminal tail that mediates autoinhibition. also binds phosphatases, including PTPN12 (PTP-PEST) and immune-cell PTPN22 (LYP/Pep), which dephosphorylate activation loop to promote Csk-binding proteins (e.g., CBP/PAG1) oligomerize within membrane microdomains, high local concentration promotes function. Purified homodimerizes in...
Here, we report that the LynB splice variant of Src-family kinase Lyn exerts a dominant immunosuppressive function in vivo, whereas LynA isoform is uniquely required to restrain autoimmunity female mice. We used CRISPR-Cas9 gene editing constrain lyn splicing and expression, generating single-isoform knockout (LynA KO ) or Autoimmune disease total mice characterized by production antinuclear antibodies, glomerulonephritis, impaired B cell development, overabundance activated cells...
Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of cancer. NEPC characterized by the loss androgen receptor (AR) signaling and transdifferentiation toward small-cell neuroendocrine (SCN) phenotypes, which results in resistance to AR-targeted therapy. resembles other SCN carcinomas clinically, histologically gene expression. Here, we leveraged phenotype scores various cell lines depletion screens from Cancer Dependency Map (DepMap) identify vulnerabilities NEPC. We...
ABSTRACT The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking dimerization and conformation we built an allosteric model inhibitor-induced that resolves the contributions inhibitor binding to two active sites dimer, revealing key differences between I inhibitors. For coupling...
Spondweni virus (SPONV) is the closest known relative of Zika (ZIKV). SPONV pathogenesis resembles that ZIKV in pregnant mice, and both viruses are transmitted by Aedes aegypti mosquitoes. We aimed to develop a translational model further understand transmission pathogenesis. found cynomolgus macaques ( Macaca fascicularis ) inoculated with or were susceptible but resistant infection. In contrast, rhesus mulatta supported productive infection developed robust neutralizing antibody responses....
Abstract The unique roles of the Src-family kinases LynA and LynB in immune activating inhibitory signaling have eluded definition. Here we report that LynB, shorter splice product lyn , carries dominant immunosuppressive function. We used CRISPR/Cas9 gene editing to constrain splicing expression a single product: KO or mice. While activities both isoforms regulate homeostatic Lyn expression, only protects against autoimmune disease. monocytes dendritic cells are TLR4-hyper-responsive, TLR4...
The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking dimerization and conformation we built an allosteric model inhibitor-induced that resolves the contributions inhibitor binding to two active sites dimer, revealing key differences between I inhibitors. For coupling...
NK cells are being extensively studied as a cell therapy for cancer. Their effector functions induced by the recognition of ligands on tumor and various cytokines. IL-15 is broadly used to stimulate endogenous adoptively transferred in cancer patients. These stimuli activate membrane protease ADAM17, which then cleaves assorted receptors surface negative feedback loop limit their activation function. We have shown that ADAM17 inhibition can enhance IL-15-mediated proliferation
Background Natural killer (NK) cells are being extensively studied as a cell therapy for cancer. These activated by recognition of ligands and antigens on tumor cells. Cytokine therapies, such IL-15, also broadly used to stimulate endogenous adoptively transferred NK in patients with stimuli activate the membrane protease ADAM17, which cleaves various cell-surface receptors negative feedback loop limit their cytolytic function. ADAM17 inhibition can enhance IL-15-mediated proliferation vitro...