The laboratory is principally involved in the study of receptor signal transduction for several growth factors and the identification of receptors that share subunits or are members of the same receptor superfamily. These growth factors primarily have effects on cells of lymphoid and hematological origin or as in the case of prolactin, breast tissue normal and transformed. The laboratory has extended its investigations into the role of the JAK/Stat pathway for specific cytokine receptors. Through critical analysis of the IL2, IL4, and prolactin receptor systems we have identified structural and functional requirements responsible for recruitment and activation of JAK and Stat proteins. Additionally, we have identified the structural requirements for the activation of collateral signal pathways associated with PI3 kinase activation and the activation of the SHC/Grb2 pathway involved in RAS activation. We have shown that the patterns of JAK kinase and Stat activation for respective receptor systems may be pleiotypically modified depending upon the state of differentiation or oncogenic progression of the cells in which the receptors are expressed. For example, breast carcinoma cell lines may exhibit profound difference in the JAK/Stat pathways utilized varying from cell line to cell line. This suggests a remarkable adaptability of the receptors to use different members of a family of enzymes to achieve significant receptor coupling and biological outcome. The laboratory has continued structure function studies through mutational analysis of JAK2 in order to determine the chemical basis of activation or repression. Further, we are examining the role of alternatively spliced variants of JAK3 with a possible role in human breast cancer cells. Several new substrates of JAK3 have been identified, a p100 protein that appears to have a novel unique protein sequence and molecular cloning experiments are underway.
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