Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported the establishment of an interleukin-3 (IL-3)-dependent and phenotypically myeloid cell line (TALL-103/3), obtained by culturing cells from an immature T-lymphoblastic leukemia in the presence of IL-3. These cells differentiated into a T-lymphoid cell line (TALL-103/2) upon removal of IL-3 and incubation in IL-2. Despite the different phenotype, the two cell lines remained karyotypically and genotypically identical. Here, we have analyzed the phenotypic changes and the signaling events induced by these two lymphokines in TALL-103/3 cells by switching them to temporary growth in IL-2 and returning them to IL-3. All four sublines obtained (the myeloid in IL-3 and the lymphoid in IL-2) expressed RNA for CD3, IL-2 receptor (R) alpha, and T-cell receptor (TCR)-gamma and -delta chains. However, cells cultured in IL-3 failed to express detectable levels of the IL-2R beta chain at both the protein and RNA levels, whereas cells exposed to IL-2 always expressed IL-2R beta. In parallel with the changes in IL-2R beta expression, the SRC-like protein tyrosine kinase (PTK) p56 LCK could not be detected in IL-3-dependent cells, but was abundant in the IL-2-dependent cells and underwent markedly increased autophosphorylation in response to IL-2. In contrast, p53/p56 LYN was highly expressed in IL-3-dependent cells, and greatly decreased when these cells were switched to growth in IL-2. LYN kinase autophosphorylation modestly increased in response to IL-3. None of the other kinases in the SRC family that were tested underwent increased autophosphorylation after lymphokine stimulation, indicating the specificity of IL-2 for LCK and of IL-3 for LYN. The TALL-103 cell lines provide a unique system to study the interaction between lymphokines and SRC-family PTKs in signal transduction pathways leading to hematopoietic cell differentiation.
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PMID:Phenotypic changes induced by interleukin-2 (IL-2) and IL-3 in an immature T-lymphocytic leukemia are associated with regulated expression of IL-2 receptor beta chain and of protein tyrosine kinases LCK and LYN. 137 47

Recently we described the establishment in culture and the immunophenotypic and functional characteristics of a human T-leukemia line TALL-103/2 derived from the T-cell receptor (TCR)-gamma/delta subset of T-lymphocytes. TALL-103/2 cells are absolutely dependent on interleukin 2 (IL-2) for their growth and survival in culture and thus provide a model cell line for studies of IL-2 signal transduction in a TCR-gamma/delta T-cell. In this report, we focus on the regulation of SRC-family protein tyrosine kinases (PTKs) by IL-2. TALL-103/2 cells were found to contain p56-LCK, p59-FYN, p62-YES and p53/56-LYN. Stimulation of growth factor-deprived TALL-103/2 cells with IL-2, however, induced increases in the relative activity only of the p56-LCK kinase. This IL-2-mediated increase in LCK kinase activity was manifested both by increased kinase autophosphorylation and by increased phosphorylation of the exogenous substrate enolase during in vitro kinase assays. Furthermore, immunoblot assays determined that the levels of p56-LCK protein were unaltered by IL-2-treatment, indicating that the measured elevations in LCK kinase activity reflected an increase in the specific activity of this PTK. In TALL-103/2 cells, IL-2 stimulated concentration-dependent increases in p56-LCK activity that displayed rapid and transient kinetics: detectable increases occurred within 1 minute after IL-2 stimulation, peaked at 10 minutes, and declined to baseline levels by 30 minutes. Treatment of TALL-103/2 cells with IL-4 abrogated IL-2-initiated proliferation, but did not inhibit IL-2-mediated activation of p56-LCK.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin 4 inhibits IL-2-induced proliferation of a human T-leukemia cell line without interfering with p56-LCK kinase activation. 142 Sep 98

IL-2 is one of the principal growth factors regulating the proliferation of T lymphocytes. Although two independent IL-2-binding molecules have been molecularly cloned and shown to participate in the formation of a high affinity receptor complex, their primary structures do not suggest a specific mechanism for IL-2 growth signal transduction across the cell membrane. Neither IL-2 receptor subunit contains an intrinsic kinase domain; nevertheless, tyrosine phosphorylation of various intracellular substrates is one of the first biochemical changes observed following activation of the IL-2 receptor (IL-2R). Both serine/threonine and tyrosine kinases can be co-precipitated as part of the IL-2R complex suggesting that the IL-2 signalling may involve the activation of non-covalently associated intracellular kinases. However, controversy exists as to which kinases are involved in IL-2 signal transduction; in particular, which kinase(s) mediates the first or proximal event(s) in the signalling process. Activation of the IL-2R leads to serine and threonine phosphorylation of the SRC tyrosine kinase family member, LCK, and an increase in LCK tyrosine kinase activity. Furthermore, LCK can be co-immunoprecipitated with the beta chain of the IL-2R indicating its association with the receptor complex. IL-2 has also been reported to increase FYN kinase activity and to alter its association with the 85 kDa subunit of phosphatidylinositol-3 kinase thus suggesting a role for FYN in IL-2 signal transduction. However, in this report, we now demonstrate that neither LCK nor FYN are obligatory for IL-2-induced growth of HTLV-I-infected human T cells. Lack of expression of LCK or FYN in the HTLV-I-infected T cell lines was demonstrated by a combination of Northern blotting, polymerase chain reaction, Western blotting, and in vitro kinase activity. Despite the absence of LCK or FYN, IL-2 induced similar patterns of rapid tyrosine phosphorylation. Similar results were observed in cell lines lacking expression of the LYN, FGR, HCK, and LTK tyrosine kinases. Thus, none of these tyrosine kinases alone appears to be required for growth signalling through the IL-2R in the HTLV-I-infected T cell lines analyzed. The findings raise the possibility that an, as yet, unidentified tyrosine kinase is involved. Alternatively, this biological signalling system may exhibit remarkable redundancy whereby several different tyrosine kinases may be capable of associating with the IL-2R complex and mediating intracellular signalling.
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PMID:Neither the LCK nor the FYN kinases are obligatory for IL-2-mediated signal transduction in HTLV-I-infected human T cells. 147 76

Unlike many other growth factor receptors, the known subunits of the receptors for the Interleukins IL-2 and IL-3 lack intrinsic tyrosine kinase activity, and yet increases in the phosphorylation of proteins on tyrosines is a rapid event in hematolymphoid cells following stimulation with these lymphokines. Here we show that IL-2 and IL-3 regulate the activity of specific members of the SRC-family of non-receptor protein tyrosine kinases (PTKs). In IL-2-dependent T-cell lines, IL-2 induced rapid and transient increases in the activity of the p56-LCK kinase without influencing the activities of other SRC-like PTKs (p59-FYN, p62-YES) in these T-lymphocytes. In contrast to IL-2's effects on p56-LCK in T-cells, studies of an IL-2-responsive cell line of the B-cell lineage that lacks p56-LCK revealed that IL-2 specifically regulates the activity of the p53/56-LYN kinase. Thus, some flexibility exists in the ability of various SRC-like PTKs to functionally couple to IL-2 signalling pathways. In several IL-3-dependent myeloid-committed leukemic cell lines, IL-3 was found to specifically regulate the activity of the p53/56-LYN kinase without affecting the activities of other SRC-like PTKs (p59/64-HCK, p59-FYN, p62-YES) in these hematopoietic cells. This finding that p53/56-LYN can be regulated by both IL-2 in B-lineage cells and IL-3 in myeloid-committed cells demonstrates that the same SRC-family PTK can participate in signal transduction events mediated via two independent receptor systems. Taken together, our findings imply that the specific combinations of lymphokine receptors and SRC-like PTKs available for coupling with those receptors are coordinately controlled during the differentiation of hematopoietic cells.
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PMID:Regulation of SRC-family protein tyrosine kinases by interleukins, IL-2, and IL-3. 160 36

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
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PMID:Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. 163 19

Activation of platelets with thrombin and other agonists causes a rapid increase in the phosphorylation of multiple proteins on tyrosine. To identify candidate protein-tyrosine kinases (PTKs; EC 2.7.1.112) that may be responsible for these phosphorylation events, we analyzed the expression of seven Src-family PTKs and examined the association of these kinases with known platelet membrane glycoproteins. Five Src-related PTKs were detected in platelets: pp60SRC, pp60FYN, pp62YES, pp61HCK, and two LYN products of Mr 54,000 and 58,000. The Fgr and Lck PTKs were not detected. Although strict comparative quantification of protein levels was not possible, pp60SRC was detected at higher levels than any of the other kinases. In addition, glycoprotein IV (GPIV, CD36), one of the major platelet membrane glycoproteins, was associated in a complex with the Fyn, Yes, and Lyn proteins in platelet lysates. Similar complexes were also found in two GPIV-expressing cell lines, C32 melanoma cells and HEL cells. Since PTKs appear to be involved in stimulus-response coupling at the plasma membrane, these results suggest that ligand interaction with GPIV may activate signaling pathways that are triggered by tyrosine phosphorylation.
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PMID:Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets. 171 82

The expression of protein-tyrosine kinases (PTKs; ATP:protein-tyrosine O-phosphotransferase, EC 2.7.1.112) was studied in normal human lung and various tumors by PCR followed by molecular cloning and sequence analysis. Six known PTKs (YES, FGR, LYN, HCK, PDGFB-R, and CSF1-R), as well as two additional members of this enzyme family, were detected in lung. One of the newly discovered sequences appears to represent a group of cytosolic PTKs. The cDNA sequence of the second unknown PTK revealed that it is a fourth member of the fibroblast growth factor receptor family. It was therefore called TKF (tyrosine kinase related to fibroblast growth factor receptor). Among a wide variety of cells and tissues tested, including human lymphocytes and macrophages, TKF was only found expressed in lung. Apart from normal lung, TKF expression could be demonstrated in some tumors of lung origin, but also in malignancies not derived from lung tissues. As fibroblast growth factors are generally involved in a variety of functions such as mitogenesis, angiogenesis, and wound healing, the specific expression of a receptor-related gene in lung only may point to yet another special function of this group of proteins.
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PMID:Two additional protein-tyrosine kinases expressed in human lung: fourth member of the fibroblast growth factor receptor family and an intracellular protein-tyrosine kinase. 172 May 39

We studied the effects on plasma levels of coagulation and fibrinolysis factors of two currently used "sub-50" oral contraceptive preparations (OCs), one containing 750 micrograms lynestrenol and 37.5 micrograms ethinyl estradiol (LYN-EE) and the other containing 150 micrograms levonorgestrel and 30 micrograms ethinyl estradiol (LNG-EE), in groups of about 25 women aged 21 +/- 2 years. After 3 months, plasminogen levels increased in the two experimental groups (LYN-EE and LNG-EE), by 40% and 32%, respectively. This change was positively correlated with changes in ceruloplasmin levels, indicating that an estrogenic effect might be involved. Histidine-rich glycoprotein concentration decreased by 26% and 16%, respectively. Tissue-type plasminogen activator (t-PA) activity increased by 260% and 167%; t-PA antigen decreased by 12% and 18%, and t-PA inhibitor activity decreased by 31% and 32%, respectively. In the coagulation system, in both groups factor XII increased by 47% and 34%, respectively. The main inhibitor of factor XII, C1-inactivator, decreased slightly, but this was significant only in the LNG-EE group. The von Willebrand factor antigen fell by 8% and 9%, whereas factor VIII activity did not change. Antithrombin III antigen decreased by 14% in both groups. Factor IX activity increased by 15% and 21%. The difference in hormonal effects of both preparations was reflected by the increases in sex hormone binding globulin (by 130% and 21%) and ceruloplasmin (by 98% and 51%), indicating that LYN-EE had a more estrogenic potency than LNG-EE. In a control group of 25 matched subjects, who were observed simultaneously, we found no significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of two low-dose oral contraceptives on circulating components of the coagulation and fibrinolytic systems. 310 29

Intravenous glucose tolerance tests (IVGTT) with simultaneous assessment of plasma insulin and analyses of the fatty acid composition of serum lecithin and cholesterol esters were performed in 11 women with previous gestational diabetes before and repeatedly during 6 months' administration of a low-dose progesterone (lynestrenol = LYN). 8 of these women were also followed in an identical manner during 6 months of nonhormonal contraception (intrauterine device = IUD) and additionally 6 of these women were followed also during the use of a combined oral contraceptive (OC) (ethinyl estradiol + lynestrenol - EE + LYN). LYN did not alter the IVGTT or plasma insulin but decreased the proportion of polyunsaturated fatty acids (PUFA) in serum lecithin (p less than 0.01) and cholesterol esters (p less than 0.01) where oleic acid was reciprocally increased (p less than 0.05). After 6 months' use of IUD, on the other hand, the k value of IVGTT increased by 45% (p less than 0.01) without significant changes in plasma insulin. In both lecithin and cholesterol ester PUFA increased (p less than 0.05) and cholesterol ester oleate decreased (p less than 0.01); i.e., virtually the reversal of the changes seen during LYN administration. The combined OC, EE + LYN, caused a decrease in the k value by 27% (p less than 0.05) which was apparent even when compared to the effects of LYN alone. EE + LYN also increased (p less than 0.05) lecithin palmitate and decreased stearate (p less than 0.05) and had a concomitant tendency to lower PUFA and increase oleic acid in both lecithin and cholesterol esters. These results indicate that LYN has little influence on the glucose tolerance in women predisposed to diabetes but may provide poorer conditions for dietary treatment of subclinical diabetes than do nonhormonal IUDs. The combined CO, EE + LYN, on the other hand, promptly diminishes glucose tolerance and may also have an unfavorable influence on liver metabolism.
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PMID:Metabolic studies in gestational diabetic women during contraceptive treatment: effects on glucose tolerance and fatty acid composition of serum lipids. 703 4

Twenty-three young women with insulin-dependent diabetes were randomly allocated to contraceptive treatment with either a progestogen only (Lynestrenol 0.5 mg) (LYN) or a combined oral contraceptive (OC) (ethinyl estradiol 50 micrograms + lynestrenol 2.5 micrograms) (EE + LYN). After six months treatment the medication was withdrawn for at least two months, after which the patients were placed on the other preparation. Diabetes control and serum and high density lipoprotein (HDL) lipids were assessed before and after 1, 3 and 6 months of treatment. Low-dose LYN administration did not alter the insulin requirement, blood glucose or body weight while the combined EE + LYN treatment increased the insulin requirement (p less than 0.01) without altering blood glucose or body weight. Low-dose LYN reduced serum triglycerides (p less than 0.001), serum cholesterol (p less than 0.001) and serum phospholipids (p less than 0.01) without affecting HDL lipids, while EE + LYN gave an inconsistent increase in serum triglycerides (p less than 0.01) but no change in HDL lipids. These findings confirm our earlier results and we conclude that EE + LYN influences diabetes control slightly more (although still not seriously) than the low-dose LYN. It is suggested that insulin-dependent diabetics (in contrast to non-diabetics) are more sensitive to the influence of 19-norprogestogens than to alkylated estrogens, with respect to lipid metabolism.
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PMID:Oral contraception in diabetic women. A cross-over study on serum and high density lipoprotein (HDL) lipids and diabetes control during progestogen and combined estrogen/progestogen contraception. 704 Jan 92


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