Research Group

  • Dr. Majed Hamawy, Principal Investigator
  • Dr. Zheng Chang, Research Associate


  • University of Wisconsin Medical School, Madison, USA


  • LAT, a Molecule Critical for T Cell Activation and Function, is a Potential Substrate for Calcineurin

Blocking the activation of the serine/threonine phosphatase calcineurin in T cells by CsA and FK506 has been useful for preventing allograft rejection in humans. Yet blocking calcineurin activation by CsA and FK506 has also been associated with side effects that limit the clinical use of these drugs. Although calcineurin inhibition blocks IL-2 production, it increases the release of cytokines such as TGF-β from T cells. Also, because calcineurin is found in almost all cells, blocking its activation does not only affect T cell function but also disrupts the function of other cells.

Given that blocking calcineurin signaling pathways has proven useful for blocking T cell activation, we initiated studies to define T-cell-specific targets for calcineurin that are important for T cell activation. The identification of these targets should be useful for designing drugs that block the activation of such targets and in turn specifically block T cell function with no or minimal side effects. We have shown that blocking calcineurin activation with CsA and FK506 increases the expression and reduces the electrophoretic mobility of LAT, a signaling molecule found predominantly in T cells that is critical for T cell activation and development. Incubation of purified calcineurin with LAT in vitro led to dephosphorylation of LAT and an increase in its electrophoretic mobility on SDS-PAGE, suggesting that LAT is a potential substrate for calcineurin. Thus, CsA and FK506, by blocking calcineurin activation, appear to regulate both the cellular level and the phosphorylation level of LAT in T cells.

We aim to identify the amino acid residues in LAT whose phosphorylation is regulated by calcineurin inhibitors, and to examine the role of these residues in T cell function. Because LAT is predominantly found in T cells, the data obtained could provide a means to design new drugs that specifically block T cell activation and prevent allograft rejection with minimal or no side effects.