David Clemmons, MD

HONORS & AWARDS

  • 2004 MERIT Award National Institutes of Health
  • 2005 Aurbach Award, Endocrine Society

    RESEARCH

    Summary:

    Receptor Signaling

    IGF-I is a growth factor that is ubiquitously present in all bodily fluids and stimulates balanced and symmetric growth in tissues. Abnormalities of IGF-I concentrations and action have been implicated in the pathogenesis of both cardiovascular disease and cancer. Our laboratory is interested in how integral membrane proteins and proteins in the pericellular environment interact with the IGF receptor to regulate IGF-I receptor linked signaling. We have shown that four integral membrane proteins and their respective ligands can modify IGF-I receptor activation. SHPS-1, a transmembrane protein with SH2 binding domains on its cytoplasmic tail is rapidly phosphorylated by the IGF-I receptor following IGF-I stimulation, and this is accompanied by the recruitment of SHP-2 phosphatase to the plasma membrane. SHP-2 then dephosphorylates SHPS-1, allowing SHP-2 to be transferred to the IGF-I receptor. SHPS-2 rapidly inactivates receptor signaling and this mechanism is believed to be important for preventing unrestrained proliferation of neoplastic cells. We are currently attempting to determine the molecular mechanism by which the transfer of SHP-2 from SHPS-1 to the receptor occurs.

    A second area of study concerns positive modulation of cellular actions by the receptor. IGF-I functions are augmented in vascular smooth muscle cells and endothelial cells when the aVb3 integrin is ligand- occupied. Conversely, blocking ligand occupancy attenuates IGF action in these cells. We have shown that the integral membrane, integrin associated protein, binds to aVb3 and enhances its affinity for ligands thereby enhancing IGF-I actions.  IGF-I functions in the regulation of this process by stimulating the translocation of integrin associated protein from lipid rafts of the plasma membrane to nonraft domains. The importance of this lies in the fact that aVb3 is localized exclusively in nonraft domains; therefore this translocation permits a 12 fold increase in the amount of IAP bound to aVb3 and a substantial increase in aVb3 affinity. Moreover, IGF-I positively modulates the responsiveness of cells to its own ligand occupancy by affecting this change. Preliminary studies indicate that trimolecular complexes may form among these four components. We are now determining the regions of each protein that are necessary for these interactions to occur. We utilized in vitro mutagenesis to disrupt the interactions that determine their effects on IGF-I signaling. Similarly each of these integral membrane proteins binds to extracellular ligands and we are currently identifying the ligands that bind with highest affinity and the biologic responses to ligand occupancy of each component. These studies will help us to formulate a much more complete picture of how IGF-I regulates cellular function.

    REPRESENTATIVE PUBLICATIONS

      • Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov. 2007 Oct;6(10):821-33
      • Miller EC, Capps BE, Sanghani RR, Clemmons DR, Maile LA. Regulation of igf-I signaling in retinal endothelial cells by hyperglycemia. Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3878-87
      • Nichols TC, Busby WH Jr, Merricks E, Sipos J, Rowland M, Sitko K, Clemmons DR. Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Endocrinology. 2007 Oct;148(10):5002-10. Epub 2007
      • Xi G, Maile LA, Yoo SE, Clemmons DR. Expression of the human beta3 integrin subunit in mouse smooth muscle cells enhances IGF-I-stimulated signaling and proliferation. J Cell Physiol. 2008 Feb;214(2):306-15.
      • Clemmons DR. IGF-I assays: current assay methodologies and their limitations. Pituitary. 2007;10(2):121-8

      CONTACT INFO

      6111A Thurston-Bowles
      Campus Box 7170
      Chapel Hill, NC 27599

      Office: 919-966-4735

      endo@email.unc.edu

      Clemmons Lab Website