Ulrike M. Lorenz, PhD
Protein tyrosine phosphatase SHP-1 in T cell development and function, and in breast cancer
Tyrosyl phosphorylation and dephosphorylation of proteins are a key regulatory mechanism in many normal signal transduction pathways leading to cell proliferation, differentiation, and death, events which are often dysregulated in cancer. The steady state level of tyrosyl phosphorylation on any protein is determined by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs).
The Lorenz lab interest focuses on the involvement of the PTP SHP-1 in signaling pathways. SHP-1 is a non-transmembrane, src homology 2 (SH2)-domain containing PTP expressed primarily in hematopoietic cells of all lineages and at lower levels in epithelial cells. The research presently ongoing in the lab can be divided into two major projects: (i) the role of SHP-1 in T cell activation and development; and (ii) the role of SHP-1 in the on-set/development of breast cancer.
(i) SHP-1 and T cell development & function.
Recently, it has become evident that so-called regulatory T cells are critical for a controlled "normal" immune response. In their absence, autoimmune diseases develop, while depletion of regulatory T cells has been shown to enhance the immune response to cancer cells. Despite a better understanding of their functional importance, is still unclear what factors/signaling pathways regulate the development of these T cells. The lab has found that SHP-1 controls signaling pathways involved in the development of regulatory T cells and that mice lacking SHP-1 show dramatically increased numbers of functionally active regulatory T cells. This identifies the first signaling molecule involved in the ontogeny of regulatory T cells and could have implications for immunotherapy of cancer.
Data obtained from the these studies should have implications for
patho-physiological T cell development and function and may provide
means for regulating uncontrolled T cell proliferation (as it is
occurring for example in T cell leukemia) or for potentiating immune
responses, for example to strengthen an immune response against cancer
These studies are performed in close contact with Dr. Ken Tung and members of his lab.
All of the studies mentioned above would not be possible without the support of the Cell Sorter Facility and the Transgenic Mouse Core.
(ii) SHP-1 and breast cancer. Mice of the C3HeB/FeJLe-a/a background, which carry the so-called me allele resulting in the absence of detectable SHP-1 protein, show an increased frequency of breast tumors (>90%) among the retired female C3HeB/FeJLe-a/a-me compared to normal C3HeB/FeJLe-a/a mice of the same age. The lab is now addressing the potential involvement of SHP-1 in the on-set/development of breast cancer. In particular, they are investigating the role of SHP-1 in the regulation of signaling events mediated by the Epidermal Growth Factor receptor (EGFR) and/or Src. They expect from these studies to gain a better understanding of the role of negative regulators in breast cancer development.