The interest of my laboratory is in defining the molecular basis for cell fate decisions triggered by plasma membrane receptors. In particular, we have focused on the translation of receptor-initiated signals as they relate to cell fate decisions leading to cell growth, survival and apoptosis. Each of these cellular processes when deregulated lead to the loss of the homeostatic balance necessary for normal tissue growth, renewal, and differentiation and, can result in cancer and autoimmunity.
Depending upon the activation state, the stage of development, or the strength of the signal, a signal generated through the B cell antigen receptor (BCR) results in very different B lymphocyte responses. For example, at the pre-B cell stage, BCR signaling triggers allelic exclusion, expansion of pre-B cells and developmental progression. In contrast, BCR signal transduction in immature-stage B cells leads either to apoptosis or editing and replacement of antigen reactive receptors. These latter processes are believed be the underlying mechanisms regulating negative selection against autoreactive specificities among immature B cells in the bone marrow and periphery. We study the molecular processes regulating the coupling of BCR signals to these specific cellular responses in order to define the processes in normal and disease prone mice that regulate positive and negative selection events during B cell development. Developmental-associated differences in BCR signal transduction and gene regulation are the laboratory's principle areas of focus in defining the biochemical and genetic processes regulating B cell development and selection.
In addition, we have recently discovered the ability of the antigen receptor on B cells to generate survival and differentiation signals independently of ligand. This ligand-independent or tonic signaling depends upon a specific protein sequence motif termed an ITAM. Signaling through ITAMs depends upon Src kinase-medicated phosphorylation of tyrosine residues encoded within these motifs. These ITAM-dependent tonic signals are held in check in hematopoietic tissues by a complex balance of positive and negative regulators whose expression are nearly exclusively restricted to cells of the hematopoietic system. The only known instances of ITAM-containing protein expression in tissues outside of the hematopoietic system are a handful of oncogenic viruses. These viruses encode transmembrane proteins that contain canonical ITAMs. Importantly, the expression of virus encoded ITAM proteins (or highly homologous sequences) have been associated with malignancies of predominately epithelial tissues in rodents and humans. In particular, Mouse Mammary Tumor Virus gp52 and homologous sequences isolated from human tumors possess these motifs and are associated with breast cancer. We have shown that ITAM-dependent signals are generated through MMTV Env and trigger early hallmarks of transformation of mouse and human mammary epithelial cells. These data suggest a heretofore unappreciated potential mechanism for the initiation of breast cancer and identify MMTV Env and ITAM-containing proteins in human breast tumors as probable oncoproteins. In addition, they represent potentially new targets for prognosis and therapy in human breast cancer. We are currently studying the molecular basis for ITAM-mediated transformation using both in vitro and in vivo experimental approaches.