- Professor, Department of Medicine
- Professor, Department of Cell Biology
- Professor, Department of Biochemistry and Molecular Pharmacology
- Director, Medical Scientist Training Program
- Director, Basic Research, Perlmutter Cancer Center
- American Board of Internal Medicine (Rheumatology), 1988
- American Board of Internal Medicine - Internal Medicine, 1985
Education and Training
- Fellowship, NYU Medical Center, Rheumatology, 1988
- Residency, NYU Medical Center, Internal Medicine, 1985
- MD from Columbia University, 1982
Research My Research
processing and membrane targeting of GTPases, cancer, immunology, pharmacology
Our laboratory is primarily interested in the cell biology of GTPases. GTPases are ubiquitous elements of signaling pathways, including those regulating cell growth and differentiation. Virtually all cellular processes utilize GTPases as regulatory elements including processes that control the immune response. Thus, although our work has immediate relevance to cancer, insights from our studies may be relevant to a wide variety of human diseases including inflammatory and autoimmune disorders.
The protooncogene ras and closely related GTPases are among a class of proteins that are synthesized as soluble molecules in the cytosol and are then targeted to membranes by a series of posttranslational modifications of a C-terminal CAAX sequence that includes prenylation, proteolysis, and carboxyl methylation. Of these modifications, only carboxyl methylation is reversible and may therefore have a signaling function. We therefore focused on the enzyme that catalyzes this modification, prenylcysteine carboxyl methyltransferase, and recently cloned its gene.
Prenylcysteine carboxyl methyltransferase proved to be a multiple membrane spanning protein that is expressed in ER and Golgi but not plasma membrane (see figure). This observation was surprising since it implied that ras, synthesized in the cytosol and destined for the plasma membrane, must make a detour to the ER to complete processing. The ER processing of ras led us to hypothesize that ras is transported to plasma membrane via the vesicular transport system. Using green fluorescent protein-tagged ras proteins we showed that this model is correct. We also showed that carboxyl methylation is required for vesicular transport of ras. We hope to exploit this previously unappreciated aspect of ras biology to develop novel anticancer therapies.
In more recent work we have tested the hypothesis that intracellular ras can be activated and regulate signaling pathways and proved it correct. We accomplished this by developing a novel fluorescent probe that reports when and where Ras becomes activated in living cells. We consider our probe for activated ras a prototyped of a class of molecules that can serve as fluorescent reporters of signaling events in living cells and thereby elucidate many previously inaccessible aspects of signal transduction.
Research Interests Timeline
Journal of medicinal chemistry. 2019 Jul 11; 62(13):6035-6046
Nature structural & molecular biology. 2019 Jul ; 26(7):628-636
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2019 Feb 26; 116(9):3524-3529