Genetic alterations are the hallmark of malignant transformation. These changes lead to the activation of cellular oncogenes or the inactivation of tumor suppressor genes. The majority of oncogenes encode proteins that are involved in cellular growth control and signal transduction within the cell. A major mechanism of protein-protein interaction involved in cell growth, differentiation, and function consists of phosphorylation- dephosphorylation, much of which occurs on tyrosine residues. Thus, one group of oncogenes of particular interest is the src family of protein tyrosine kinases. Recently, a new member of the src family of tyrosine kinase genes, blk, has been identified. The blk gene was shown to be expressed solely in B-lymphoid cells; however, little is known about the regulatory mechanisms involved in its tissue restricted expression. In addition, the structure and function of the protein tyrosine kinase, p55blk, encoded by this gene and the role of p55blk in B-cell signal transduction in normal and malignant B-cells has not been established. Thus, the objective of the research proposed in this application is to elucidate the structure, regulation, and function of the human p55blk protein tyrosine kinase in normal B lymphocytes as well as in B- cell malignancies.
The specific aims are to: (1) identify functional regions and residues of p55blk involved in catalysis and signal transduction; (2) determine the structure and regulation of the human blk gene, including the identification of cis acting control elements and transacting regulatory factors; (3) identify and characterize proteins that interact with p55blk, including substrates of its kinase activity as well as other kinases and phosphatases that regulate its activity; and (4) determine the role of p55blk in the growth of normal and malignant human B lymphocytes.
