D45 is the major transmembrane tyrosine phosphatase of the immune system and is highly expressed by all hematopoietic cells 1 . The best described role for CD45 is in antigen receptor signal transduction. In this case, the phosphatase activity of CD45 appears to be required for activation of Src-family kinases associated with antigen receptors 2 . By contrast, CD45 inhibits activation of Src-family kinases in macrophages and some lymphocyte lines [3][4][5] . Here, we discuss the observations that CD45 is both a positive and negative regulator of Src-family kinases depending upon receptor interaction.
Regulation of Src-family kinases
In leukocytes, CD45 is an important regulator of Src-family kinases. The Src-family is a group of intracellular tyrosine kinases that interact with cell membranes via lipid modification and amino acids at the amino-terminus. However, interaction with specific receptors is mediated by protein-protein interactions. Each of the nine known family members comprises five regions: (1) an N-terminal region that is highly divergent between family members; (2) an Src-homology 2 (SH2) domain; (3) an SH3 domain; (4) the catalytic domain (SH1); and (5) a short Cterminal tail (Fig. 1). Regulation of Src-family members occurs via multiple mechanisms including tissue expression, subcellular localization, lipid modification at the unique amino-terminus, interactions of the SH2 and SH3 domains, and phosphorylation. In this article, we will concentrate on regulation of Src kinases by tyrosine phosphorylation.
Src kinases have two principal regulatory tyrosine phosphorylation sites (Fig. 1). Phosphorylation within the kinase domain potentiates kinase activity, whereas phosphorylation within the C-terminal tail inhibits kinase activity. When expressed in cells, Src-family kinases that contain a mutation of tyrosine to phenylalanine at the inhibitory phosphorylation site have increased kinase activity and contribute to transformation (reviewed in Ref. 6). Indeed, the v-Src transforming protooncogene, a viral Src-family member, does not contain the inhibitory phosphorylation site. The resolution of the crystal structures of c-Src and Hck has helped defined the mechanism by which tyrosine phosphorylation regulates activity 7,8 . Phosphorylation of the Cterminal inhibitory site allows it to form an intramolecular association 10