Location

Rochester, Minnesota

Contact

Shapiro.Virginia1@mayo.edu

Summary

Currently there are two primary areas of investigation in my lab, both of which have involved the generation of unique lines of knockout mice. One area involves the study of the transcriptional repressor NKAP, that is a component of the Notch corepressor complex and negative regulator of Notch. The second area is the biochemical mechanisms that mediate T cell activation, and we cloned an adaptor molecule, ALX, that is a negative regulator of T cell activation. These projects are outlined in greater detail below. Notch comprises a family (Notch 1-4 in mammals) of transmembrane receptors. Notch proteins function in many cell fate decisions. In the immune system, Notch signaling controls the generation of hematopoietic stem cells, the T vs B lineage decision, the beta-selection checkpoint during T cell development and the Th1/Th2 lineage decision. In the absence of Notch signaling, a transcriptional corepressor complex keeps Notch targets off. Utilizing a genetic screen, we identified a novel component of the Notch corepressor complex, NKAP. To understand the function of NKAP in vivo, we generated conditional knockout mice. Deletion of NKAP during T cell development (lck-cre NKAP conditional knockout mice), blocks T cell development at the beta-selection checkpoint, resulting in a 25-fold decrease in DP T cells. NKAP is also critical to proper hematopoiesis. Loss of NKAP in hematopoietic stem cells (vav-cre NKAP conditional knockout mice) results in a severe block in multiple hematopoietic lineages. Thus, NKAP, like Notch, regulates the development and function of many lineages in the immune system. Our current work continues to investigate the requirement for NKAP throughout hematopoieis. Much of the published work from our laboratory to date has focused on the function of an adaptor molecule, ALX, in regulating T cell activation. Mice deficient in ALX are hyper-responsive to TCR/CD28 signaling, resulting in increased production of IL-2 and increased proliferation. Biochemically, loss of ALX results in constitutive activation of MKK3/6 and p38 map kinase pathways. ALX associates with the transmembrane adaptor LAX, and together ALX and LAX function to negatively regulate T cell activation. Our current work is focused on understanding the biochemical mechanism behind ALX and LAX function in T cells, and the role these proteins play in regulating T cell responsiveness.

Recent Publications

See my publications

Professional Details

Primary Appointment

  1. Immunology

Academic Rank

  1. Associate Professor of Immunology

Education

  1. Post Doctoral Fellowship - CD28-mediated regulation of the IL-2 promoter through the RE/AP composite element University of California, San Francisco
  2. PhD - Molecular and Cell Biology University of California, Berkeley
  3. AB - Biochemistry (magna cum laude) Harvard University
.
BIO-00097048

Mayo Clinic Footer