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Mark Ginsberg, MD

Professor Adjunct
Department of Molecular Medicine
California Campus
Scripps VIVO Scientific Profile
(858) 784-9465

Research Focus

Integrin Structure and Function:
Ligand Binding and Inside-Out Signaling

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 lead 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 anayzed and the capacity of one of those interactions to regulate integrin activation has been established. 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. 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 an anti-apoptotic protein, PEA-15 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 transport. 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.

Professional Experience

2004-2017 Professor Adjunct, Cell and Molecular Biology (CMB), The Scripps Research Institute

Awards & Professional Activities

BCMP Lecture, Department of Cell Biology, Harvard University, Boston, Massachusetts; Editorial Boards, Journal of Biological Chemistry, Molecular Biology of the Cell, Journal of Cell Science.

Selected References

All Publications

Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, Ginsberg MH, Calderwood DA. 2003. Talin binding to integrin tails: a final common step in integrin activation. Science 302, 103-106.

Chou FL, Hill JM, Hsieh JC, Pouyssegur J, Brunet A, Glading A, Uberall F, Ramos JW, Werner MH, Ginsberg MH. 2003. PEA-15 binding to ERK1/2 MAP kinases is required for its modulation of integrin activation. J Biol Chem. 278,52587-52597

Goldfinger, L.E., J. Han, W.B. Kiosses, A.K. Howe, and M.H. Ginsberg. 2003. Spatial restriction of alpha 4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration. J.Cell Biol. 162:731-741

Calderwood, D.A., Y. Fujioka, Y., J.M. de Pereda, B.Garcia-Alvarez, T. Nakamoto, B. Margolis, C. J. McGlade, R.C. Liddington and M.H. Ginsberg. 2003. Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: A structural prototype for diversity in integrin signaling. Proc. Natl. Acad. Sci.100:2272-2277