A5003355400- Cellular transport and secretion
- Protein Kinase Regulation and GTPase Signaling
- Fungal and yeast genetics research
- Ubiquitin and proteasome pathways
- Ion channel regulation and function
- Metabolism, Diabetes, and Cancer
- PI3K/AKT/mTOR signaling in cancer
- Microtubule and mitosis dynamics
- Pancreatic and Hepatic Oncology Research
- Epigenetics and DNA Methylation
- Cancer, Hypoxia, and Metabolism
- Pancreatic function and diabetes
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- 14-3-3 protein interactions
- Biotin and Related Studies
- Protein Degradation and Inhibitors
- Sports injuries and prevention
- Mitochondrial Function and Pathology
- Cancer-related Molecular Pathways
- Hedgehog Signaling Pathway Studies
- Signaling Pathways in Disease
- RNA Research and Splicing
- Peptidase Inhibition and Analysis
- Antifungal resistance and susceptibility
University of Sheffield
2005-2025
NYU Langone Health
2011-2021
NYU Langone’s Laura and Isaac Perlmutter Cancer Center
2019
New York University
2009-2017
Cancer Institute (WIA)
2013
Institute of Cell Biology
2013
Cardiff University
2003
Significance The KRAS oncogene is mutated more frequently in human cancer than any other. transcript alternatively spliced to give rise two products, K-Ras4A and K-Ras4B, both of which are oncogenic when mutated. We detected significant amounts each tumor cells colorectal carcinomas. found that targeted the plasma membrane by dual targeting motifs distinct from those K-Ras4B. Because interfering with association Ras proteins remains one most attractive approaches anti-Ras therapy, efforts...
Fungi grow with a variety of morphologies: oval yeast cells, chains elongated cells called pseudohyphae and long, narrow, tube-like filaments hyphae. In filamentous fungi, hyphal growth is strongly polarised to the tip mediated by Spitzenkörper, which acts as supply centre concentrate delivery secretory vesicles tip. budding Saccharomyces cerevisiae, polarisome, surface cap proteins that nucleates formation actin cables delivering growing The human fungal pathogen, Candida albicans, can in...
Significance K-Ras is mutated more often than any other oncogene, making the protein and pathways it regulates attractive targets for anticancer drug discovery. We have shown that phosphorylation of serine 181 in membrane-targeting region causes to translocate from plasma membrane intracellular membranes. Translocation associated with toxicity but mechanism has remained undefined. Here we show phospho–K-Ras associates inositol trisphosphate receptors (IP3Rs) on endoplasmic reticulum (ER)...
The human fungal pathogen Candida albicans can switch between yeast, pseudohyphal, and hyphal morphologies. To investigate whether the distinctive characteristics of hyphae are due to increased activity Cdc42 GTPase, strains lacking negative regulators were constructed. Unexpectedly, deletion Rho guanine dissociation inhibitor RDI1 resulted in reduced rather than enhanced polarized growth. However, when cells both GTPase-activating proteins, encoded by RGA2 BEM3, grown under...
RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed Pdx1-Cre;LSL-KrasG12D mouse, which model pancreatic ductal adenocarcinoma (PDA), with mouse harboring floxed allele Icmt. Surprisingly, we found that ICMT deficiency...
Isoprenylcysteine carboxyl methyltransferase (Icmt) is a highly conserved enzyme that methyl esterifies the α group of prenylated proteins including Ras and related GTPases. Methyl esterification neutralizes negative charge prenylcysteine thereby increases membrane affinity. Icmt an integral protein restricted to endoplasmic reticulum (ER). The Saccharomyces cerevisiae ortholog, Ste14p, traverses ER six times. We used novel fluorescent reporter map topology human in living cells. Our results...
Isoprenylcysteine carboxyl methyltransferase (ICMT) methylesterifies C-terminal prenylcysteine residues of CaaX proteins and some RAB GTPases. Deficiency either ICMT or NOTCH1 accelerates pancreatic neoplasia in
Isoprenylcysteine carboxyl methyltransferase (ICMT) is the third of three enzymes that sequentially modify C-terminus CaaX proteins, including RAS. Although all four RAS proteins are substrates for ICMT, each traffics to membranes differently by virtue their hypervariable regions differentially palmitoylated. We found among NRAS was unique in requiring ICMT delivery PM, a consequence having only single palmitoylation site as its secondary affinity module. not absolutely required...
Abstract Ras proteins are targeted to membranes by virtue of post-translational modifications their C-terminal hypervariable regions (HVRs). Because signal only when associated with cellular membranes, the trafficking pathway is considered an attractive area for anti-cancer drug discovery. The three mammalian genes, hras, nras and kras, give rise four because transcript kras locus alternatively spliced encode K-Ras4A K-Ras4B. most often mutated in human cancer gives oncogenic forms both...