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PubMed1992

Effects of bolus doses of fat on small intestinal structure and on release of gastrin, cholecystokinin, peptide tyrosine-tyrosine, and enteroglucagon.

To investigate the enterotrophic effects of bolus doses of long chain triglycerides, two groups of eight female Wistar rats were fed identical diets with 48.2% total calories as the essential fatty acid rich oil Efamol. To one group the oil was given in twice daily bolus doses by gavage, while for the other group the oil was mixed with the remainder of the feed and thus consumed over 24 hours. The animals were killed after 20 to 22 days. Bolus dosing significantly increased parameters of mucosal mass along the length of the small intestine in association with an increase in two hour accumulation of vincristine arrested metaphases in small intestinal crypts. In a second experiment, four replicate studies were carried out, each involving two groups of 12 rats respectively fed as described above. After 21 days one animal from each group was killed every two hours, providing regular plasma samples over 24 hours for measurement of gastrin, cholecystokinin, peptide tyrosine-tyrosine and enteroglucagon. Bolus dosing markedly enhanced release of peptide tyrosine-tyrosine and enteroglucagon, but not of gastrin or cholecystokinin. Thus, the enhanced enterotrophic effects of bolus doses of long chain triglycerides could be mediated by release of a distally located gut peptide, perhaps enteroglucagon.

Animals↗
PubMed1991

A functional complex is formed in human T lymphocytes between the protein tyrosine phosphatase CD45, the protein tyrosine kinase p56lck and pp32, a possible common substrate.

In vitro protein kinase assays of CD45 immunoprecipitates prepared from digitonin lysates of resting human T lymphocytes resulted in exclusive tyrosine phosphorylation of a 32-kDa protein (pp32). Reprecipitation of the in vitro phosphorylated proteins and Western blot analysis of whole CD45 immunoprecipitates employing antisera specifically directed at different protein tyrosine kinases demonstrated that the p56lck protein tyrosine kinase was responsible for in vitro phosphorylation of pp32. Since in vitro kinase assays of p56lck immunoprecipitates also resulted in phosphorylation of pp32, the present data strongly suggest that a functional complex is formed between CD45, p56lck and pp32. Such a notion is supported by the findings that phosphorylation of pp32 by p56lck correlated with expression of the CD45 molecules and that in vitro phosphorylated pp32 was completely dephosphorylated by purified CD45.

Antigens, CD↗
PubMed1994

Analysis of Ig-alpha-tyrosine kinase interaction reveals two levels of binding specificity and tyrosine phosphorylated Ig-alpha stimulation of Fyn activity.

The B cell antigen receptor complex (BCR) is composed of membrane Ig and heterodimers of Ig-alpha and Ig-beta/gamma. Recent findings indicate that Ig-alpha associates with Src-family kinases, including Fyn and Lyn, via an approximately 26 amino acid motif termed ARH1. Studies reported here (i) define two mechanisms whereby this motif binds Fyn and (ii) reveal an important functional consequence of binding, i.e. kinase activation. Mutational analysis indicates that specific low-affinity binding is determined by a short sequence, -DCSM-, in the motif and is not dependent on motif tyrosine residues. In contrast, the doubly tyrosine phosphorylated motif binds independently of DCSM and with high affinity. Importantly, this binding leads to Fyn activation. Taken together with studies which map low-affinity binding of Fyn or Lyn to the kinase's N-terminal unique region and high-affinity binding to the kinase's SH2 domain, these results suggest a mechanism of BCR activation in which the non-phosphorylated resting receptor is associated with Src-family kinases and, upon stimulation, tyrosine phosphorylation of Ig-alpha leads to reorientation and activation of receptor-associated kinases.

3T3 Cells↗
PubMed1994

The angiotensin II AT1 receptor is tyrosine and serine phosphorylated and can serve as a substrate for the src family of tyrosine kinases.

Angiotensin II AT1 receptor signal transduction has recently been shown to function through the phospholipase C isozyme, PLC-gamma. Since PLC-gamma is known to interact with phosphotyrosine containing proteins through SH2 domains, we examined the phosphorylation state of the AT1 receptor. Immunoprecipitation of the [32P] labeled AT1 receptor from rat aortic smooth muscle cells followed by alkali hydrolysis demonstrated the presence of tyrosine phosphorylation. Phosphoamino acid analysis of the excised bands demonstrated the presence of phosphoserine and phosphotyrosine residues. A fusion protein comprising the intracellular tail of the AT1 receptor was used to screen for candidate kinases, and the src kinase family displayed high activity. In summary, this study shows that the AT1 receptor is serine and tyrosine phosphorylated in vivo and suggests that a soluble kinase related to the src family may be responsible for the tyrosine phosphorylation.

Angiotensin II↗
PubMed1988

Numerous proteins phosphorylated on tyrosine and enhanced tyrosine kinase activities in vanadate-treated NIH 3T3 fibroblasts.

A monoclonal antibody that can immunoprecipitate proteins containing phosphotyrosine has been isolated and characterized. To identify proteins that can act as substrates for tyrosine kinases in intact cells, extracts of phosphate-labeled NIH cells that had been treated with the phosphotyrosyl phosphatase inhibitor, vanadate, were precipitated with the antibody, and the immunoprecipitates were analyzed by two-dimensional gel electrophoresis. Numerous proteins were specifically precipitated from vanadate-treated NIH 3T3 cells by the antibody. The high level of phosphotyrosine detected in vanadate-treated cells is presumably primarily due to phosphatase inhibition, but approx. 2-fold increased tyrosine kinase activities were also detected in extracts of the cells after treatment with vanadate. The enhanced tyrosine kinase activity may contribute to the generation of the transformed phenotype seen in response to treatment with vanadate.

Animals↗
PubMed1994

Evaluation of 3-[18F]fluoro-alpha-fluoromethyl-p-tyrosine as a tracer for striatal tyrosine hydroxylase activity.

3-[18F]Fluoro-alpha-fluoromethyl-p-tyrosine (3-F-FMPT) was evaluated as a tracer for CNS tyrosine hydroxylase (TH) activity in rodents and in a rhesus monkey. Results of in vitro experiments using rat striatal homogenates showed that the introduction of fluorine into the 3-phenyl position did not significantly alter the ability of FMPT to act as a TH-activated L-aromatic amino acid decarboxylase (L-AAAD) inhibitor. These studies further showed that 3-F-FMPT-induced L-AAAD inhibition was dose-dependent. Furthermore, striatal homogenates prepared from rats pretreated with the potent TH inhibitor alpha-methyl-p-tyrosine was found to have diminished 3-F-FMPT-induced L-AAAD inhibition. However, despite these promising in vitro results, the biodistribution of this compound in mice showed low brain uptake and fast clearance through the kidneys. A PET study using a Rhesus monkey injected with 3-[18F]F-FMPT confirmed the results obtained in mice, i.e. negligible brain uptake but high localization in the bladder. We conclude that 3-[18F]F-FMPT would not be useful as a tracer for cerebral TH activity.

Animals↗
PubMedDate not supplied

Synthesis and anti-tyrosine kinase activity of 3-(substituted-benzylidene)-1, 3-dihydro-indolin derivatives: investigation of their role against p60c-Src receptor tyrosine kinase with the application of receptor docking studies.

A series of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-thione derivatives were synthesized as modified congeners of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-one series. All the synthesized compounds were examined for their in vitro anti-tyrosine kinase activity against p60c-Src. The activity results revealed that compounds (Z)-3-(4'-Dimethylamino-benzylidene)-1, 3-dihydro-indolin-2-thione (12) (E)-3-(2', 6'-Dichloro-benzylidene)-1, 3-dihydro-indolin-2-thione (13) and (E)-3-(3'-Hydroxy-4'-methoxy-benzylidene)-1, 3-dihydro-indolin-2-thione (19) exhibited anti-tyrosine kinase activity with IC50 value of 21.91, 21.20 and 30.92 microM, respectively. These results are comparable to PP1 [1-tert-Butyl-3-p-tolyl-1H-pyrazolo[3, 4-d]pyrimidine-4-yl-amine] (IC50=0.17 microM), which is reported as a potent and selective p60c-Src tyrosine kinase inhibitor. Some thio congeners are found to be more potent than oxo derivatives; however, no significant correlation was observed between the activity profiles of these two series. Docking program was used to investigate the docking mode of each compound at the active site. Among all of the compounds, only (Z)-3-(2'-Chloro-benzylidene)-1, 3-dihydro-indolin-2-one (8) and (E)-3-(3'-Nitro-benzylidene)-1, 3-dihydro-indolin-2-thione (16) were docked at the active site where the PP1 was embedded.

Amino Acid Sequence↗
PubMed2005

Crystal structure of a complex between protein tyrosine phosphatase 1B and the insulin receptor tyrosine kinase.

Protein tyrosine phosphatase 1B (PTP1B) is a highly specific negative regulator of insulin receptor signaling in vivo. The determinants of PTP1B specificity for the insulin receptor versus other receptor tyrosine kinases are largely unknown. Here, we report a crystal structure at 2.3 A resolution of the catalytic domain of PTP1B (trapping mutant) in complex with the phosphorylated tyrosine kinase domain of the insulin receptor (IRK). The crystallographic asymmetric unit contains two PTP1B-IRK complexes that interact through an IRK dimer interface. Rather than binding to a phosphotyrosine in the IRK activation loop, PTP1B binds instead to the opposite side of the kinase domain, with the phosphorylated activation loops sequestered within the IRK dimer. The crystal structure provides evidence for a noncatalytic mode of interaction between PTP1B and IRK, which could be important for the selective recruitment of PTP1B to the insulin receptor.

Cloning, Molecular↗
PubMed1989

Receptor cross-linking restores an insulin metabolic effect altered by mutation on tyrosine 1162 and tyrosine 1163.

The pivotal role that the tyrosine residues in positions 1162 and 1163 play in the control of the insulin action has been clearly established by substitution of these tyrosine residues for phenylalanine [Ellis, L. (1986) Cell 45, 721-732]. We have recently found that this type of mutation, which abolishes the effects of insulin on glucose metabolism, was without any effect on the mitogenic effect of the hormone [Debant, A. (1988) Proc. Natl. Acad. Sci. U.S.A. (in press)]. Here, we provide evidence that a polyclonal antibody, raised against the human insulin receptor, can restore the receptor-mediated stimulation of glycogen synthesis that was abolished by the mutation. Stimulation of the biological effect by the anti-receptor antibody did not necessitate, whatsoever, the activation of the tyrosine kinase activity and/or receptor autophosphorylation. Furthermore, the antibody-induced reversal of the mutation was not observed when we used Fab fragments alone, but addition of anti-(Fab')2 IgG in a second step resulted in a similar effect as that observed with intact IgG. We propose that Tyr 1162 and Tyr 1163 exert their control on the metabolic effects of insulin through the modulation of receptor aggregation.

Animals↗
PubMed1996

Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1.

Protein tyrosine phosphorylation plays a key role in regulating eukaryotic cell proliferation and differentiation. Genetic analysis in invertebrates has been invaluable for dissecting the signalling events downstream of receptor tyrosine kinases (RTKs). We have used this approach in mammals to analyse the interactions between the Kit RTK encoded by the murine Dominant white spotting (W) locus and the Shp1 protein tyrosine phosphatase, the product of the murine motheaten (me) gene. Homozygosity for mutations in both W and me ameliorates aspects of both the me and W phenotypes, including the lethal lung disease associated with me and the embryonic lethality and mast cell deficiency associated with W, demonstrating that the Kit receptor plays a role in the pathology of the me phenotype and conversely that Shp1 negatively regulates Kit signalling in vivo.

Anemia↗
PubMed1997

ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK)

Anaplastic Lymphoma Kinase (ALK) was originally identified as a member of the insulin receptor subfamily of receptor tyrosine kinases that acquires transforming capability when truncated and fused to nucleophosmin (NPM) in the t(2;5) chromosomal rearrangement associated with non-Hodgkin's lymphoma, but further insights into its normal structure and function are lacking. Here, we characterize a full-length normal human ALK cDNA and its product, and determine the pattern of expression of its murine homologue in embryonic and adult tissues as a first step toward the functional assessment of the receptor. Analysis of the 6226 bp ALK cDNA identified an open reading frame encoding a 1620-amino acid (aa) protein of predicted mass approximately 177 kDa that is most closely related to leukocyte tyrosine kinase (LTK), the two exhibiting 57% aa identity and 71% similarity over their region of overlap. Biochemical analysis demonstrated that the approximately 177 kDa ALK polypeptide core undergoes co-translational N-linked glycosylation, emerging in its mature form as a 200 kDa single chain receptor. Surface labeling studies indicated that the 200 kDa glycoprotein is exposed at the cell membrane, consistent with the prediction that ALK serves as the receptor for an unidentified ligand(s). In situ hybridization studies revealed Alk expression beginning on embryonic day 11 and persisting into the neonatal and adult periods of development. Alk transcripts were confined to the nervous system and included several thalamic and hypothalamic nuclei; the trigeminal, facial, and acoustic cranial ganglia; the anterior horns of the spinal cord in the region of the developing motor neurons; the sympathetic chain; and the ganglion cells of the gut. Thus, ALK is a novel orphan receptor tyrosine kinase that appears to play an important role in the normal development and function of the nervous system.

Amino Acid Sequence↗
PubMed1993

Thrombin and thrombin receptor agonist peptide induce tyrosine phosphorylation and tyrosine kinases in the platelet cytoskeleton. Translocation of pp60c-src and integrin alpha IIb beta 3 (glycoprotein IIb/IIIa) is not required for aggregation, but is dependent on formation of large aggregate structures.

The maximal aggregation of platelets induced by alpha-thrombin or by the receptor agonist peptide thrombin-(42-47)-peptide (TRP42/47) rapidly increased the pp60c-src associated with the cytoskeleton fraction. There was good correlation between the tyrosine kinase activity and the mass of pp60c-src. Tyrosine kinase activity associated with the cytoskeleton phosphorylated several endogenous cytoskeleton-associated proteins, as revealed by immunoblotting with anti-phosphotyrosine antibody following incubation with ATP in vitro. However, with the exception of pp60c-src, few phosphotyrosine-containing proteins were retained in the cytoskeleton in intact platelets when compared with total platelet lysates. Translocation of pp60c-src to the cytoskeleton induced by alpha-thrombin and TRP42/47 is dependent on glycoprotein IIb/IIIa (GPIIb/IIIa)-fibrinogen-mediated aggregation, but does not occur when ristocetin/von Willebrand factor produces GPIb-mediated platelet aggregation. The translocation of GPIIb/IIIa and pp60c-src to the cytoskeleton is not necessary for aggregation, as it is not seen when clearly visible small to moderate-sized aggregates are initially formed after exposure to thrombin. The linkage of these proteins to the cytoskeleton occurs only after later extensive formation of large aggregates. Translocation of GPIIa/IIIa to the cytoskeleton is not sufficient for the cytoskeletal association of pp60c-src, as the former occurs independently in platelets stimulated with concanavalin A in the absence of aggregation. Linkage of the integrin GPIIb/IIIa and pp60c-src to the internal cytoskeleton structure, and the corresponding tyrosine phosphorylation of certain proteins upon formation of large aggregates, may be an example of mechanochemical transduction by integrin receptors and may represent a structure with the requisite tensile strength to stabilize large platelet aggregates against high shear stresses.

Amino Acid Sequence↗
PubMed1991

Two additional protein-tyrosine kinases expressed in human lung: fourth member of the fibroblast growth factor receptor family and an intracellular protein-tyrosine kinase.

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.

Amino Acid Sequence↗
PubMed1995

CD38 ligation induces tyrosine phosphorylation of Bruton tyrosine kinase and enhanced expression of interleukin 5-receptor alpha chain: synergistic effects with interleukin 5.

Mouse CD38 has been implicated in the regulation of both B-cell proliferation and protection of B cells from irradiation-induced apoptosis. CD38 ligation on B cells by CS/2, an anti-mouse CD38 monoclonal antibody, induced proliferation, IgM secretion, and tyrosine phosphorylation of Bruton tyrosine kinase in B cells from wild-type mice. B cells from X chromosome-linked immunodeficient mice did not respond at all to anti-CD38 antibody, although CD38 expression on these B cells was comparable to that on wild-type B cells. We infer from these results that Bruton tyrosine kinase activation is involved in B-cell triggering after cross-linkage of CD38. Analysis of the synergistic effects of various cytokines with CD38 ligation on B-cell activation revealed that interleukin 5 (IL-5) showed the most potent effect on B-cell proliferation, Blimp1 gene expression, and IgM production. These synergistic effects were not seen with B cells from X chromosome-linked immunodeficient mice. Flow cytometry analysis revealed that CD38 ligation increased surface expression of the IL-5-receptor alpha chain on B cells. These data indicate that CD38 ligation increases IL-5 receptor alpha expression and synergizes with IL-5 to enhance Blimp1 expression and IgM synthesis.

ADP-ribosyl Cyclase↗
PubMed1998

Low molecular weight protein-tyrosine phosphatase tyrosine phosphorylation by c-Src during platelet-derived growth factor-induced mitogenesis correlates with its subcellular targeting.

The low molecular weight phosphotyrosine phosphatase (LMW-PTP) is an enzyme that is involved in the early events of platelet-derived growth factor (PDGF) receptor signal transduction. Our previous results have shown that LMW-PTP is able to specifically bind and dephosphorylate activated PDGF receptor, thus modulating PDGF-induced mitogenesis. In particular LMW-PTP is involved in pathways that regulate the transcription of the immediately early genes myc and fos in response to growth factor stimulation. In this study we have established that, in nontransformed NIH3T3 cells, LMW-PTP exists constitutively in cytosolic and cytoskeleton-associated localization and that, after PDGF stimulation, c-Src is able to bind and to phosphorylate LMW-PTP only in the cytoskeleton-associated fraction. As a consequence of its tyrosine phosphorylation, LMW-PTP significantly increases its catalytic activity. After PDGF stimulation these two LMW-PTP pools act on distinct substrates, contributing in different manners to the PDGF receptor signaling. The cytoplasmic LMW-PTP fraction exerts its well known action on activated PDGF receptor. On the other hand we have now demonstrated that the cytoskeleton-associated LMW-PTP acts specifically on a few not yet identified proteins that become tyrosine-phosphorylated in response to the PDGF receptor activation. Finally, these two LMW-PTP pools markedly differ in the timing of the processes in which they are involved. The cytoplasmic LMW-PTP pool exerts its action within a few minutes from PDGF receptor activation (short term action), while tyrosine phosphorylation of cytoskeleton-associated LMW-PTP lasts for more than 40 min (long term action). In conclusion LMW-PTP is a striking example of an enzyme that exerts different functions and undergoes different regulation in consequence of its subcellular localization.

3T3 Cells↗
PubMed2002

Regulation of signaling in B cells through the phosphorylation of Syk on linker region tyrosines. A mechanism for negative signaling by the Lyn tyrosine kinase.

The B cell antigen receptor (BCR) is coupled to the mobilization of Ca(2+) by the protein-tyrosine kinase, Syk. Syk, recruited to the clustered BCR, becomes phosphorylated on three tyrosines (Tyr-317, Tyr-342, and Tyr-346) located within the linker region that separates the C-terminal catalytic domain from the N-terminal tandem Src homology 2 domains. Phosphorylation within the linker region can be either activating or inhibitory to Ca(2+) mobilization depending on the sites that are modified. Syk that is not phosphorylated on linker region tyrosines couples the BCR to Ca(2+) mobilization through a phosphoinositide 3-kinase-dependent pathway. The phosphorylation of Tyr-342 and -346 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of Ca(2+) mobilization via a phosphoinositide 3-kinase-independent pathway. The phosphorylation of Tyr-317 strongly dampens the Ca(2+) signal. In cells that lack the Src family kinase, Lyn, the phosphorylation of the inhibitory Tyr-317 is suppressed leading to elevated production of inositol 1,4,5-trisphosphate and an amplified Ca(2+) signal. This provides a novel mechanism by which Lyn functions as an inhibitor of BCR-stimulated signaling. Thus, Syk and Lyn combine to determine the pathway through which the BCR is coupled to Ca(2+) mobilization as well as the magnitude and duration of the Ca(2+) flux.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Role of the activation loop tyrosines in regulation of the insulin-like growth factor I receptor-tyrosine kinase.

The tyrosine kinase activity of insulin-like growth factor I receptor (IGF1R) is under tight control. Ligand binding to the extracellular portion of IGF1R stimulates autophosphorylation at three sites (Tyr1131, Tyr1135, and Tyr1136) in the activation loop within the tyrosine kinase catalytic domain. Autophosphorylation at all three sites is required for maximum enzyme activity, and for IGF1-stimulated cellular activity of the receptor. Previous studies have not clarified the contributions of the individual tyrosines to enzymatic activation. Here, we produced single Tyr-to-Phe mutations at these positions, and compared activities of the purified kinase domains (unphosphorylated and phosphorylated) with wild-type IGF1R. Rates of autophosphorylation of the three mutants were more rapid than for wild-type IGF1R; this was most apparent for the Y1135F mutant. Substrate phosphorylation studies on the unphosphorylated forms of IGF1R confirmed that the value of Vmax for Y1135F was elevated relative to wild-type IGF1R, consistent with a disruption of an autoinhibitory interaction. In contrast, activity measurements on the fully phosphorylated enzymes indicated that kcat/Km values were lowered relative to wild-type IGF1R; this effect was most dramatic for Y1136F. We confirmed these findings using limited proteolysis and tryptophan fluorescence experiments. The results demonstrate that Tyr1135 plays a particularly important role in stabilizing the autoinhibited conformation of the activation loop, while Tyr1136 plays the key role in stabilizing the open, activated conformation of IGF1R.

Catalytic Domain↗