Mark Ginsberg

Affiliation: UCSD SOM

Professor of Medicine

mhginsberg@ucsd.edu
Phone: (858)822-6432

Biography

Mark H. Ginsberg, M.D. performed his undergraduate studies at McGill University in Montreal, Canada, where he was a University Scholar. He was awarded an M.D., summa cum laude, from the State University of New York, Downstate Medical Center. He performed his internship and residency in Internal Medicine at the University of Chicago from 1970-1973, and from 1973-75 was a postdoctoral fellow in Rheumatology at the same university. In 1975, Dr. Ginsberg came to The Scripps Research Institute as a postdoctoral fellow and moved his way up to his present position as a full Professor in the Departments of Vascular Biology and Cell Biology. Dr. Ginsberg was instrumental in the discovery and analysis of the integrin adhesion receptor family. He is the author of more than 200 original scientific publications, largely devoted to the study of integrins. He has served on the Executive and Nominating Committees of the Council on Thrombosis and numerous Federal and non-Federal peer review bodies. Dr. Ginsberg has served as an Associate Editor of the Journal of Clinical Investigation and on the editorial boards of Blood, the Journal of Biological Chemistry, Thrombosis and Haemostasis, Trends in Cardiovascular Medicine, the Journal of Cell Science, and Molecular Biology of the Cell. He is a member of Alpha Omega Alpha, the American Society of Clinical Investigation, and the American Association of Physicians. He has received numerous honors including the Boris Muskatov Prize, a Research Career Development Award and MERIT Award from the NIH, and an Investigator Recognition Award from the International Society for Thrombosis and Haemostasis.

Research Summary

The interactions between cells and their surrounding extracellular matrix play a central role in the development of multi-cellular animals. Early studies from our lab established that the matrix protein, fibronectin, binds to specific cell surface receptors. These receptors are members of a widely distributed protein family, now termed integrins. This protein family is essential for the normal development and functioning of both vertebrates and invertebrates. Many integrins recognize short peptide sequences in proteins such as fibrinogen and fibronectin. These peptides can therefore inhibit integrin function and represent prototypes of a novel class of therapeutics. Furthermore, we used a combination of biochemical and genetic approaches to map ligand binding sites in integrins and to understand the mechanism of binding.

Integrin receptors also transmit information in both directions across the plasma membrane. For example, the anchorage dependence of cell growth is mediated by signals emanating from integrins. Conversely, intracellular signaling events are reflected on the cell surface by changes in the conformation and ligand binding affinity of integrin receptors. This process, termed "inside-out" signal transduction, seems to be a general property of this receptor family. Inside-out signaling not only controls adhesive functions, but also regulates cell migration and the assembly of an extracellular fibronectin matrix. Integrin cytoplasmic domains play a central role in integrin activation. Conversely, when integrins bind ligands they change conformation and long range propagation of these conformational changes leads to intracellular signaling events. Integrin signaling into cells also depends on their cytoplasmic domains. To understand the structure of the cytoplasmic domains and how they interact with intracellular partners to generate integrin-dependent signals we've utilized a combination of synthetic and recombinant approaches to generate model protein mimics of the integrin cytoplasmic domains. Through the use of these model proteins the interactions of integrins with the actin cytoskeleton have been anayzed40 and the capacity of one of those interactions to regulate integrin activation has been established.

Models of the physical links between integrins and F-actin. When known, the modular architecture of the linking proteins is shown based on domain assignments by the SMART program . The integrin tail is depicted binding to ERM domains within the talin head domain; however, integrin-binding sites have also been identified in the rod domain. The spectrin repeats within the a actinin rod domain mediate binding to the integrin tail; however, it is not known which of the three repeats contains the binding site. Filamin binds integrins via C-terminal filamin repeats; however, the exact binding site has not yet been determined.

Furthermore, a4 integrins play a pivotal role in chronic inflammation because they markedly enhance the migration of leukocytes. The cytoplasmic domains of a4 integrins bind an adaptor, paxillin, via a central 9 amino acid motif. This interaction accounts for the unusual signaling properties of this integrin. A current focus is to understand how paxillin binding to a4 regulates cellular behaviors and to analyze the mechanisms of regulation and consequences of the integrin interactions with actin binding proteins, such as talin. In addition, a major emphasis will be on the effects of these interactions on the structure of these tails, as we now know that structural analysis of the model proteins is accessible by multi-dimensional nuclear magnetic resonance spectroscopy. We have developed genetic strategies for analysis of integrin signaling that depends on the use of integrin affinity for extracellular ligands as a selectable marker. This method has been validated for use in integrin structure-function studies, and for somatic cell genetic approaches to analyze signaling pathways. In addition, such a strategy was used to develop novel expression cloning schemes that defined a new pathway involve the suppression of integrin activation by activated H-Ras via a MAP kinase pathway. This pathway is probably involved in the control of cell migration and may be dysregulated during malignant transformation (See some data). More recent studies have established that the activity of this pathway can be opposed by another Ras family member, R-Ras via an apparently novel effector. A current focus is to understand the downstream events in this suppressor pathway and to identify the R-Ras effectors responsible for reversal of suppression. The suppressor pathway can also be opposed by a an anti-apoptotic protein, PEA-15 46 even though PEA-15 promotes the activity of the ERK MAP kinase pathway. We therefore have an active interest in identification of binding partners of PEA-15 and to understand how this protein can regulate MAP kinase signaling In another expression cloning scheme, complementation of dominant suppression, implicated a regulator of amino acid transport, CD 98, in integrin signaling. CD98 binds to integrin cytoplasmic domains and distinct domains of this protein are responsible for its effects on integrins and amino acid transport50. A current focus is to analyze the mechanism by which CD 98 regulates integrins by analysis of mice with a disruption of the CD98 gene and recently derived CD98 null ES cells.

References

References From PubMed (NCBI)