A5030579510- Cancer-related Molecular Pathways
- Computational Drug Discovery Methods
- Protein Kinase Regulation and GTPase Signaling
- HER2/EGFR in Cancer Research
- PI3K/AKT/mTOR signaling in cancer
- Cancer Treatment and Pharmacology
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Epigenetics and DNA Methylation
- Nitric Oxide and Endothelin Effects
- Advanced Breast Cancer Therapies
- Glutathione Transferases and Polymorphisms
- Cancer Mechanisms and Therapy
- Cancer, Hypoxia, and Metabolism
- Cytomegalovirus and herpesvirus research
- Receptor Mechanisms and Signaling
- Cytokine Signaling Pathways and Interactions
- Estrogen and related hormone effects
- Cellular transport and secretion
- Microtubule and mitosis dynamics
- Cancer, Lipids, and Metabolism
- Renin-Angiotensin System Studies
- Adenosine and Purinergic Signaling
- Sulfur Compounds in Biology
- Cellular Mechanics and Interactions
Fox Chase Cancer Center
2013-2022
Yale University
1993-2022
Brookhaven National Laboratory
2022
The University of Texas Health Science Center at Houston
2016-2017
Robert Cizik Eye Clinic
2016-2017
University of Health Science
2017
Baylor College of Medicine
2004-2014
Philadelphia University
2014
Cornell University
2007-2013
University of Iowa
2006-2009
Structural coverage of the human kinome has been steadily increasing over time. The structures provide valuable insights into molecular basis kinase function and also a foundation for understanding mechanisms inhibitors. There are large number in PDB which Asp Phe DFG motif on activation loop swap positions, resulting formation new allosteric pocket. We refer to these as "classical DFG-out" conformations order distinguish them from that have referred DFG-out literature but do not fully...
Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety cancers, but mechanisms resistance to BETis remain poorly understood. Using mass spectrometry approach that globally measures kinase signaling at proteomic level, we evaluated response kinome targeted BETi panel BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects BETi, OC cells acquired following sustained with JQ1. Through...
Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid are reduced glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, therapeutic potential triggering ferroptosis in cancer cells fatty acids unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as inducers. αESA does not alter activity but incorporated into cellular lipids promotes peroxidation cell death diverse types....
The soluble, calcium-binding protein calreticulin shares high sequence homology with calnexin, a transmembrane chaperone of glycoprotein folding. Our experiments demonstrated that calreticulin, like associated transiently numerous newly synthesized proteins in the endoplasmic reticulum. population bound to was partially overlapping those calnexin. Hemagglutinin (HA) influenza virus shown associate both and Using HA as model substrate, it found calreticulin- calnexin-bound corresponded...
Eukaryotic protein kinases are generally classified as being either tyrosine or serine-threonine specific. Though not evident from inspection of their primary sequences, many display a significant preference for serine threonine the phosphoacceptor residue. Here we show that residue located in kinase activation segment, which term "DFG+1" residue, acts major determinant phosphorylation site specificity. Mutation this was sufficient to switch multiple kinases, including serine-specific PAK4...
The p21-activated kinases (Paks) serve as effectors of the Rho family GTPases Rac and Cdc42. six human Paks are divided into two groups based on sequence similarity. Group I (Pak1 to -3) phosphorylate a number substrates linking this group regulation cytoskeleton both proliferative anti-apoptotic signaling. II (Pak4 -6) thought play distinct functional roles, yet their few known also targeted by Paks. To determine if recognize target sequences, we used degenerate peptide library method...
p21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4–6) regulate a wide variety of cellular functions, and PAK deregulation has linked to tumor development. Structural comparison five high-resolution structures comprising all active, monophosphorylated group catalytic domains revealed surprising degree plasticity, including number catalytically productive nonproductive conformers. Rearrangements helix αC, key regulatory element...
Kinases are important therapeutic targets in oncology due to their frequent deregulation cancer. Typical ATP-competitive kinase inhibitors, however, also inhibit off-target kinases that could lead drug toxicity. Allosteric inhibitors represent an alternative approach achieve greater selectivity, although examples of such compounds few. Here, we elucidate the mechanism action IPA-3, allosteric inhibitor Pak activation. We show IPA-3 binds covalently Pak1 regulatory domain and prevents binding...
The renin-angiotensin system exerts a tremendous influence over fluid balance and arterial pressure. Angiotensin II (Ang-II), the effector peptide of system, acts in central nervous to regulate neurohumoral outflow thirst. Dysregulation Ang-II signaling is implicated cardiovascular diseases; however, mechanisms remain poorly understood. Recently we established that NADPH oxidase (Nox)–derived superoxide acting forebrain subfornical organ critical physiological responses Ang-II. In addition,...
Hypertension, a powerful risk factor for stroke and dementia, has damaging effects on the brain its vessels. In particular, hypertension alters vital cerebrovascular control mechanisms linking neural activity to cerebral perfusion. experimental models of slow-developing hypertension, free radical signaling in subfornical organ (SFO), one forebrain circumventricular organs, is critical hormonal release sympathetic activation driving elevation arterial pressure. However, contribution this...
Abstract Protein and lipid kinases play key regulatory roles in a number of biological processes. Unsurprisingly, activating mutations have been linked to disorders diseases, most notably cancers. Thus, emerged as promising clinical targets. There are more than 500 human protein about 20 kinases. Most share highly conserved domain, the eukaryotic kinase (ePK) which contains ATP substrate‐binding sites. Many inhibitors use bind binding site. For this reason, many not exclusively selective for...
Cell motility requires the spatial and temporal coordination of forces in actomyosin cytoskeleton with extracellular adhesion. The biochemical mechanism that coordinates filamentous actin (F-actin) assembly, myosin contractility, adhesion dynamics, to maintain balance between contraction remains unknown. In this paper, we show p21-activated kinases (Paks), downstream effectors small guanosine triphosphatases Rac Cdc42, biochemically couple leading-edge dynamics focal (FA) dynamics....
Several metabolic enzymes undergo reversible polymerization into macromolecular assemblies. The function of these assemblies is often unclear but in some cases they regulate enzyme activity and homeostasis. guanine nucleotide biosynthetic inosine monophosphate dehydrogenase (IMPDH) forms octamers that polymerize helical chains. In mammalian cells, IMPDH filaments can associate micron-length Polymerization are regulated part by binding purine nucleotides to an allosteric regulatory domain....
Shiga toxin 1 and 2 production is a cardinal virulence trait of enterohemorrhagic Escherichia coli infection that causes spectrum intestinal systemic pathology. However, sites E. colonization during the human how toxins are taken up cross globotriaosylceramide (Gb3) receptor-negative epithelial cells remain largely uncharacterized. We used samples tissue from patients with O157:H7 to detect bacterial characterize distribution toxins. further model Gb3-negative T84 monolayers treated...
Cyclooxygenase (COX)-derived prostanoids have long been implicated in blood pressure (BP) regulation. Recently prostaglandin E(2) (PGE(2)) and its receptor EP(1) (EP(1)R) emerged as key players angiotensin II (Ang II)-dependent hypertension (HTN) related end-organ damage. However, the enzymatic source of PGE(2,) that is, COX-1 or COX-2, site(s) action are not known. The subfornical organ (SFO) is a forebrain region mediates systemic Ang II-dependent HTN via reactive oxygen species (ROS). We...