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

---

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

Protein tyrosine kinases (PTKs) mediate signals that respond to many pivotal cellular functions. Tyrosine phosphorylation, controlled by the coordinated actions of protein tyrosine phosphatases (PTPs) and PTKs, is a critical control mechanism for various physiological processes, including cell growth, differentiation, metabolism, cell cycle regulation and cytoskeleton function. The focal adhesion kinase (FAK) is a widely expressed non-receptor tyrosine kinase that is implicated in integrin-mediated signaling and plays a role in signal transduction pathways mediating cell adhesion, motility and anchorage-independent growth. Recently, we and others have identified a novel protein tyrosine kinase termed RAFTK, (also known as Pyk2 or Cak-beta), which is related to FAK. This review describes the role of RAFTK in various signaling cascades mainly in reference to hematopoietic cell lineages.
...
PMID:Characterization of the novel focal adhesion kinase RAFTK in hematopoietic cells. 940 24

Abnormal erythropoietin (EPO)-independent cell growth is induced after infection of erythroid progenitor cells with a polycythemic strain of Friend virus (FVp). Binding of its Env-related glycoprotein (gp55) to the EPO receptor (EPOR) mimics the activation of the EPOR with EPO. We investigated the gp55-EPOR signaling in erythroblastoid cells from mice infected with FVp and in cells of FVp-induced or gp55-transgenic-mouse-derived erythroleukemia cell lines, comparing it with the EPO-EPOR signaling in EPO-responsive erythroblastoid cells. While the Janus protein tyrosine kinase JAK2 and the transcription factor STAT5 became tyrosine phosphorylated with the EPO stimulation in EPO-responsive erythroblastoid cells from anemic mice, JAK1 and STAT5 were constitutively tyrosine phosphorylated in all of these FVp gp55-induced erythroblastoid or erythroleukemic cells. Moreover, this constitutively tyrosine-phosphorylated STAT5 was unable to bind to its specific DNA sequences and did not translocate to the nucleus. Nuclear translocation and DNA binding of this STAT5 species required EPO stimulation. These findings clearly indicate that the FVp gp55-EPOR signaling is distinct from the EPO-EPOR signaling and suggest that STAT5 may not play an essential role in the transmission of the cell growth signals in FVp gp55-induced erythroleukemia cells.
...
PMID:Erythropoietin and Friend virus gp55 activate different JAK/STAT pathways through the erythropoietin receptor in erythroid cells. 948 32

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a 13-amino-acid peptide with a variety of physiological effects, including the stimulation of melanocyte proliferation and melanogenesis, temperature control, control of prolactin release and the modulation of cytokine action in the immune system. There are five known subtypes of G-protein-coupled receptors, which bind with different affinities to alpha-MSH. This paper provides evidence that Ba/F3 pro-B-lymphocyte cells express the gene for the melanocortin 5 (MC5) receptor and specifically bind alpha-MSH. Western-blot analysis reveals that alpha-MSH binding stimulates Janus kinase 2 (JAK2) and signal transducers and activators of transcription (STAT1) tyrosine phosphorylation in both Ba/F3 cells and human cultured IM-9 lymphocytes. alpha-MSH is further revealed to activate JAK2 in mouse L-cells stably expressing the human MC5 receptor. Finally, alpha-MSH binding is shown to result in an enhancement of cellular proliferation. These findings identify a new protein tyrosine kinase pathway in the action of alpha-MSH, and suggest that alpha-MSH plays an important role in B-lymphocyte function via the activation of the same intracellular phosphorylation pathway used by cytokines and growth factors.
...
PMID:Binding of alpha-melanocyte-stimulating hormone to its G-protein-coupled receptor on B-lymphocytes activates the Jak/STAT pathway. 951 81

B43 (anti-CD19)-genistein immunoconjugate targets genistein, a naturally occurring protein tyrosine kinase-inhibitory isoflavone to the membrane-associated antiapoptotic CD19-LYN complexes and triggers apoptotic cell death. In this preclinical study, the toxicity profiles of B43-genistein as well as unconjugated genistein were evaluated in cynomolgus monkeys. B43-genistein and genistein were administered either as single bolus injections or daily injections for 5-10 consecutive days via the i.v. route to monkeys. Neither genistein nor B43-genistein was toxic to cynomolgus monkeys, and no test article-related histopathological lesions were found in any of the two genistein-treated or five B43-genistein-treated cynomolgus monkeys. B43-genistein showed a favorable pharmacokinetics in monkeys, with a plasma half-life of 10-23 h. Plasma samples from B43-genistein-treated monkeys elicited potent and CD19 antigenspecific antileukemic activity against human CD19+ leukemia cells in vitro. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a tyrosine kinase inhibitor-containing immunoconjugate in nonhuman primates.
...
PMID:In vivo toxicity and pharmacokinetic features of B43 (anti-CD19)-genistein immunoconjugate in nonhuman primates. 951 66

In order to know the function of protein tyrosine kinases (PTKs) in the development of sea urchin embryos, we performed reverse transcription-polymerase chain reaction (RT-PCR) to obtain partial cDNA fragments for PTK genes using primers to highly conserved regions of the PTK family. A total of seven PTK sequences were identified, two of which represented receptor PTK (RTK1 and RTK2), and five of which were non-receptor PTKs (NRTK1-5). RTK1 was highly similar to FGF receptor and Ret kinase, while RTK2 showed features of the insulin receptor family. NRTK1 and 2 belonged to the Src family and could be involved in egg activation at fertilization. NRTK3 showed the features of the Btk family kinases, while NRTK4 seemed to be a member of the Syk/ZAP70 family. NRTK5 is the Csk-type kinase of the sea urchin, which is known to negatively regulate the Src family kinases. RTK1 was not detected in unfertilized eggs and was activated after blastula stage. All the other PTK genes were expressed both maternally in unfertilized eggs and zygotically after fertilization, though each gene showed distinct temporal patterns.
...
PMID:The protein tyrosine kinases of the sea urchin Anthocidaris crassispina. 952 Jun 36

Granulocyte macrophage-colony stimulating factor (GM-CSF) regulates the growth and differentiation of hematopoietic cells and is also involved in angiogenesis. The induction of protein tyrosine phosphorylation is critical for cytokines and growth factor-mediated signal transduction. The protein tyrosine kinase (PTK), JAK2 is involved in signaling through a number of cytokine receptors, including GM-CSF receptors. In the present study, we investigated the effect of GM-CSF on the cell cycle and protein tyrosine phosphorylation in a human endothelial cell-derived cell line, EA.hy 926 cells. GM-CSF induced the cell cycle progression and tyrosine phosphorylation of cellular proteins including JAK2 kinase in EA.hy 926 cells. Herbimycin A, a PTK inhibitor, completely blocked the GM-CSF-induced cell cycle progression, protein tyrosine phosphorylation and JAK2 kinase activation in EA.hy 926 cells. Our results demonstrate that protein tyrosine phosphorylation and JAK2 kinase activation are closely related to the GM-CSF-mediated signal transduction and growth in vascular endothelial cells, and suggest the efficacy of herbimycin A in controlling angiogenesis.
...
PMID:Signal transduction of granulocyte macrophage-colony stimulating factor in a human endothelium-derived cell line. 955 Jan 27

On the basis of the efficient substrate for p60c-src protein tyrosine kinase (PTK) YIYGSFK-NH2 (1) (Km = 55 microM) obtained by combinatorial methods, we have designed and synthesized a series of conformationally and topographically constrained substrate-based peptide inhibitors of this enzyme, which showed IC50 values in the low-micromolar range (1-3 microM). A "rotamer scan" was performed by introducing the four stereoisomers of beta-Me(2')Nal in the postulated interaction site of the peptide inhibitor 23(IC50 = 1.6 microM). This substitution led to selective and potent inhibitors of p60c-src PTK; however, no substantial difference in potency was observed among them. This and the results of the "stereochemical scan" performed at residues 2 and 7 of 3 (peptides 19-21), which form the disulfide bond, may suggest that the enzyme active site does not have rigid topographic requirements and thus is able to achieve important conformational changes to bind the ligand as long as the pharmacophore pattern in the inhibitor is conserved. Two new potent iodo-containing nonphosphorylatable tyrosine analogues were also incorporated into our lead inhibitory sequence 23, producing the most potent inhibitors for p60c-src PTK identified thus far in our studies. Compounds 29 and 30 exhibit IC50 values of 0.13 and 0.54 microM, respectively. Peptide 29 is 420-fold more potent than the parent peptide 1. Selectivity studies of peptides 23-30 toward p60c-src, Lyn, and Lck PTK showed in general high Lyn/Src and moderate Lck/Src selectivity ratios. We found that the chi1 space constraints of the specialized amino acids, introduced at position 3 of the peptide lead 23, were not as important as the configuration of the Calpha of that residue to recognize the subtle chemical environment surrounding the active site of Src and Lck PTK, as reflected on the obtained Lck/Src selectivity ratios.
...
PMID:Discovery of a novel series of potent and selective substrate-based inhibitors of p60c-src protein tyrosine kinase: conformational and topographical constraints in peptide design. 963 58

We examined the inhibitory effects of N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD), a novel antibacterial substance from the immunized adult Sarcophaga peregrina (flesh fly), on protein phosphorylation using immune complexes of protein tyrosine kinases (PTKs) with anti-PTKs monoclonal antibody. We found that 5-S-GAD directly inhibited not only tyrosine phosphorylation of PTK p60(v-src), but also tyrosine phosphorylation of PTK p210(BCR-ABL). The inhibitory potency of 5-S-GAD was comparable to that of radicicol and herbimycin A of PTK inhibitor.
...
PMID:Inhibitory effects of 5-S-GAD on phosphorylation of V-SRC and BCR-ABL tyrosine kinase. 970 70

B43(anti-CD19)-Genistein immunoconjugate targets genistein, a naturally occurring protein tyrosine kinase inhibitory isoflavone to the membrane-associated anti-apoptotic CD19-LYN complexes and triggers apoptotic cell death. In this preclinical study, the toxicity profiles of B43-Genistein as well as unconjugated genistein were evaluated in mice. B43-Genistein and genistein were administered either as single bolus injections or daily injections for 10 consecutive days via the intraperitoneal route to mice. Genistein was not toxic to mice at the highest dose of 40 mg/kg and no test article-related histopathological lesions were found in any of the 64 genistein-treated mice. B43-Genistein had a significantly longer elimination half-life and slower plasma and tissue clearance than unconjugated genistein. B43-Genistein was not toxic to mice at the highest single dose of 40 mg/kg or highest cumulative dose of 100 mg/kg and no test article-related histopathological lesions were found in any of the 108 mice treated with B43-genistein. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a tyrosine kinase inhibitor-containing immunoconjugate.
...
PMID:In vivo toxicity and pharmacokinetic features of B43(Anti-CD19)-Genistein immunoconjugate. 971 69

Basic fibroblast growth factor (FGF-2) functions as a natural inducer of mesoderm, regulator of cell differentiation and autocrine modulator of cell growth and transformation. The FGF-2 signals are transduced through receptors with intrinsic protein tyrosine kinase activity. However, receptor binding and activation is governed by extracellular matrix, cell surface or soluble proteoglycans. This paper focuses on the role of proteoglycans synthesized by embryonic cells, embryoglycans, in FGF-2 signaling via FGF receptor-1 (FGFR-1). We found that embryoglycan ectodomain Lewis X, analog of developmentally regulated embryonic cell surface epitope TEC 1, promotes oligomerization of FGF-2 in the cell free chemical crosslinking. In vitro assays show that a large molar excess of extracellular Lewis X does not inhibit binding of FGF-2 to embryonic stem (ES) cells, but prevents the mitogenic effect of FGF-2. Western blot analysis of ES cells revealed the presence of abundant 52 kDa and trace amounts of 67 and 125 kDa isoforms of FGFR-1. However, none of these isoforms undergo any detectable changes in tyrosine phosphorylation under the conditions that modulate the mitogenic effect of FGF-2. Rather, a primary substrate of all receptor tyrosine kinases, phospholipase C gamma (PLC gamma), is activated by both FGF-2 and Lewis X. The combination, FGF-2 plus Lewis X, leads to weak inhibition, when compared with the effects of FGF-2 and Lewis X, respectively. In accordance, the level of phosphorylation of non-receptor tyrosine kinase c-Src is reduced in a reversed pattern to PLC(gamma). Furthermore, in this particular cell type we show the presence of activated forms of extracellular signal-related kinase (ERK) in all nontreated and treated cells. These findings demonstrate that embryoglycan ectodomains may act as negative regulators of FGF-2-induced ES cell proliferation, most likely through the FGFR-1-independent signaling pathway.
...
PMID:Embryoglycan ectodomains regulate biological activity of FGF-2 to embryonic stem cells. 973 Sep 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---