Department of Medicine

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Faculty Profile

• Faculty List
  • Adamson
  • Ball
  • Bazhenova
  • Boles
  • Carrera
  • Carrier
  • Castro
  • Cavenee
  • Curtin
  • Daniels
  • Fanta
  • Feramisco
  • Ginsberg
  • Helsten
  • Herbst
  • Holman
  • Howell
  • Jamieson
  • Kaushansky
  • Kipps
  • Kirmani
  • Kolodner
  • Millard
  • Muchmore
  • Parker
  • Pilz
  • Read
  • Reid E
  • Reid T
  • Schwab
  • Shattil
  • Varki
  • Varner
  • Wachsman
  • Wang
  • Zanetti

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Education and Training

Psychology	McGill University, Montreal, Canada	1965
MD (Summa cum laude)	State University of NY	1970
Intern/Resident	University of Chicago	1970-1973
Rheumatology Fellow	University of Chicago	1973-1975

 

Research Interests

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 1; 2. These receptors are members of a widely distributed protein family3-5, 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 therapeutics6-9. Furthermore, we used a combination of biochemical and genetic approaches to map ligand binding sites in integrins and to understand the mechanism of binding10-18.

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 receptors19; 20. 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 migration21,22 and the assembly of an extracellular fibronectin matrix23. Integrin cytoplasmic domains play a central role in integrin activation24-26. Conversely, when integrins bind ligands they change conformation27-29and long range propagation30of these conformational changes leads to intracellular signaling events31. Integrin signaling into cells also depends on their cytoplasmic domains26,32-37. 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 synthetic38 and recombinant36,37,39,40 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 established37. 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 motif36,41. This interaction accounts for the unusual signaling properties of this integrin36,41. 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 spectroscopy42.

 

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 pathways17. 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 pathway43. 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 effector44,45. 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 pathway47. 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 signaling48. CD98 binds to integrin cytoplasmic domains49 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.

 

Publications

Lim CJ, Han J, Yousefi N, Ma Y, Amieux PS, McKnight GS, Taylor SS, Ginsberg MH. Alpha-4 integrins are type l cAMP-dependent protein kinase-anchoring proteins. Nat Cell Biol, 2007;4:415-421.

Petrich BG, Fogelstrand P, Partridge AW, Yousefi N., Ablooglu AJ, Shattil SJ, Ginsberg MH. The antithrombotic potential of selective blockade of talin-dependent integrin {alpha}llb{beta}3 (platelet GPllb-llla) activation. J Clin Invest, 2007;117:2250-2259.

Prager GW, Feral CC, Kim C, Han J, Ginsberg MH. CD98hc (SLC3a2) interaction with the integrin beta subunit cytoplasmic domain mediates adhesive signaling. J Biol Chem, 2007;282:24472.
Rose DM, Alon R, Ginsberg MH. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev, 2007;218:126-134.

Wegener KL, Partridge A, Han J, Pickford AR, Liddington RC, Ginsberg MH, Campbell ID. Structural basis of integrin activation by talin. Cell, 2007;128:171-182.

Feral CC, Rose DM, Han J, Fox N, Silverman GJ, Kaushansky K, Ginsberg MH. Blocking the alpha 4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site. J Clin Invest, 2006;116:715-723.

Goldfinger LE, Ptak C, Jeffrey ED, Shabanowitz J, Hunt DF, Ginsberg MH. RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration. J. Cell Biol, 2006;174:877-888.

Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B, Calderwood DA, Puzon-McLaughlin W, Lafuente EM, Boussiotis VA, Shattil SJ, Ginsberg MH. Reconstructing and deconstructing agonist-induced activation of integrin alphallbeta3. Curr Biol, 2006;16:1796-1806.

Kummer C, Ginsberg MH. New approaches to blockade of alpha4-integrins, proven therapeutic targets in chronic inflammation. Biochem Pharmacol, 2006;72:1460-1468.

Alon R, Feigelson SW, Manevich E, Rose DM, Schmitz J, Overby DR, Winter E, Grabovsky V, Ginsberg MH. {alpha}4{beta} 1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the {alpha}4-cytoplasmic domain. J Cell Biol, 2005;171:1073-1084.

Laboratory