Here, we have studied the activity of a novel proteintyrosine kinase inhibitor that is selective for the Src family of tyrosine kinases. We have focused our study on the effects of this compound on T cell receptor-induced T cell activation, a process dependent on the activity of the Src kinases Lck and FynT. This compound is a nanomolar inhibitor of Lck and FynT, inhibits anti-CD3-induced protein-tyrosine kinase activity in T cells, demonstrates selectivity for Lck and FynT over ZAP-70, and preferentially inhibits T cell receptor-dependent anti-CD3-induced T cell proliferation over non-T cell receptor-dependent phorbol 12-myristate 13-acetate/interleukin-2 (IL-2)-induced T cell proliferation. Interestingly, this compound selectively inhibits the induction of the IL-2 gene, but not the granulocyte-macrophage colonystimulating factor or IL-2 receptor genes. This compound offers a useful new tool for examining the role of the Lck and FynT tyrosine kinases versus ZAP-70 in T cell activation as well as the role of other Src family kinases in receptor function.
src family tyrosine kinases contain two noncatalytic domains termed src homology 3 (SH3) and SH2 domains. Although several other signal transduction molecules also contain tandemly occurring SH3 and SH2 domains, the function of these closely spaced domains is not well understood. To identify the role of the SH3 domains of src family tyrosine kinases, we sought to identify proteins that interacted with this domain. By using the yeast two-hybrid system, we identified p62, a tyrosine-phosphorylated protein that associates with p21ras GTPase-activating protein, as a src family kinase SH3-domain-binding protein. Reconstitution of complexes containing p62 and the src family kinase p59fyn in HeLa cells demonstrated that complex formation resulted in tyrosine phosphorylation of p62 and was mediated by both the SH3 and SH2 domains of p59fyn. The phosphorylation of p62 by p59fyn required an intact SH3 domain, demonstrating that one function of the src family kinase SH3 domains is to bind and present certain substrates to the kinase. As p62 contains at least five SH3-domain-binding motifs and multiple tyrosine phosphorylation sites, p62 may interact with other signalling molecules via SH3 and SH2 domain interactions. Here we show that the SH3 and/or SH2 domains of the signalling proteins Grb2 and phospholipase C gamma-1 can interact with p62 both in vitro and in vivo. Thus, we propose that one function of the tandemly occurring SH3 and SH2 domains of src family kinases is to bind p62, a multifunctional SH3 and SH2 domain adapter protein, linking src family kinases to downstream effector and regulatory molecules.
A five-year intervention study of the feasibility and effectiveness of a program aimed at the primary prevention of chronic disease was initiated in 1980 among children in 22 elementary schools in the Bronx, New York. Schools randomly were assigned either to the intervention program or to a control group. The intervention program consists of a curriculum focusing on nutrition, physical fitness, and cigarette smoking prevention. The study population at baseline comprised 2,283 fourth-graders. Subjects were eligible at baseline and at one-year follow-up for participation in a medical examination in which the following target risk factors were measured: systolic and diastolic blood pressures, plasma total and high-density lipoprotein (HDL) cholesterol, serum thiocyanate, ponderosity index, triceps skinfold thickness, and postexercise pulse recovery rate. After one year of intervention, systolic pressure increased less in the intervention group than among controls. Diastolic pressure decreased in both groups, but more in the intervention subjects than in controls. Total cholesterol decreased in the intervention group while increasing among controls. Significant net changes in the favorable direction also were observed for total cholesterol/HDL cholesterol ratio and for thiocyanate. These observations indicate that it is feasible to implement a school-based program aimed at the primary prevention of chronic disease. The intervention program appears to have had a favorable effect on several target risk factors. Although the effects were relatively small, intervention programs in schools may prove to be effective in lowering chronic disease risk.
Epidermal growth factor (EGF) causes rapid increases in free intracellular Ca2' and stimulates the phosphorylation of 11 cytosolic proteins in hepatocytes.
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