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Results for “Signal Transduction”

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PubMed2005

[Stat 3 signal transduction pathway correlates with proliferation of vascular smooth muscle cells of rats].

OBJECTIVE: To investigate the role of Stat3 (one of the signal transductant and activator) signal transduction pathway in proliferation of vascular smooth muscle cells (VSMCs). METHODS: VSMC was transfected with Stat3 antisense oligonucleotide. ELISA analysis was performed on Stat3 expression in cultured rat thoracic VSMC. Cell proliferation and toxicity assay by Methyl Thiazole (MTT) was used to measure the cell proliferation. The expression of Stat3, p-Stat3, Cyclin D1 and Bcl-x(L) were measured by Western blot. RESULTS: Stat3 protein expression was positive in VSMC. Targeting of Stat3 using antisense oligonucleotide directed against the translation site, resulted in significant growth inhibition and downregulation of Stat3, p-Stat3 and Cyclin D1. CONCLUSIONS: The increase of Stat3 correlates significantly with cell proliferation of VSMC. Cyclin D1 may be the critical target gene in mediating proliferation. Blocking Stat3 signal transduction pathway may inhibit the growth of VSMCs.

Animals↗

PubMed1990

Metalloregulatory proteins and molecular mechanisms of heavy metal signal transduction.

This review has considered what is known about the precise chemical mechanisms involved in the signal transduction of heavy metal ions. By reviewing what is known about general modes of signal transduction, we may draw parallels with the detection of and response to metal ions. In all forms of signal transduction, sensors and transducers are required. Yet, it is apparent that each system has unique features which undoubtedly are critical for the specific signal at hand. Within the context of metal-responsive systems, regardless of whether or not the metal ion is being sequestered, directly utilized, removed or otherwise, several examples of specific metalloregulatory proteins have been elucidated and are summarized in Table II. A close inspection of Table II reveals that in most signal transduction pathways for heavy metals, the presence of the metal ion causes a marked change in the nucleic acid binding capacity of the metalloregulatory protein. For example, the presence of iron results in the dissociation of a protein from iron responsive elements, thereby derepressing ferritin translation. In other instances, metal binding allows a metalloregulatory protein to associate with DNA to activate or repress transcription, as with ACE1 and Fur, respectively. In fact, to the authors' knowledge, it appears that all characterized ligand-responsive transcription factors change nucleic acid binding activity upon ligand binding. This change in affinity is a major feature of the mechanism for activation or repression by these receptors. In contrast, the mercuric ion metalloregulatory protein, MerR, operates by an entirely different transduction mechanism. MerR remains bound to its operator sequence in the presence and absence of mercuric ion, with only a slight increase in the dissociation rate constant in the presence of Hg(II). Furthermore, the site of MerR binding to the DNA is in a novel position for a prokaryotic activator, directly between the two sets of recognition sequences for RNA polymerase. Analysis of the protein-DNA interactions and transcriptional activity has demonstrated that MerR forms a complex with RNA polymerase in the absence of Hg(II) that is unstable and transcriptionally repressed. When Hg(II) is present in greater than nanomolar concentrations, a highly active transcription complex is formed at PT and a distortion at the center of the palindromic MerR binding site is detectable. Kinetic analysis has determined that, although no change in the binding of RNAP to PT is apparent, the presence of Hg(II) stimulates the rate of isomerization from the closed to the open transcription complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Dissection of the interferon gamma-MHC class II signal transduction pathway reveals that type I and type II interferon systems share common signalling component(s).

We have used a herpes virus thymidine kinase (HSV-TK) based metabolic selection system to isolate mutants defective in the interferon gamma mediated induction of the MHC class II promoter. All the mutations act in trans and result in no detectable induction of MHC and invariant chain (Ii) gene expression. Scatchard analysis indicates that the mutants have a normal number of surface IFN gamma receptors with the same affinity constant. The mutants fall into two broad categories. One class of mutants is still able to induce MHC class I, IRF-1, 9-27, 1-8 and GBP genes by IFN gamma. A second class of mutants is defective for the IFN gamma induction of all the genes tested; surprisingly, the IFN alpha/beta induction of MHC class I, 9-27, ISG54 and ISG15 genes is also defective in these mutants, although different members of this class can be discriminated by the response of the GBP and IRF-1 genes to type I interferons. These data demonstrate that the signalling pathways of both type I and type II interferon systems share common signal transduction component(s). These mutants will be useful for the study of IFN gamma regulation of class II genes and Ii chain, and to elucidate molecular components of type I and type II interferon signal transduction.

Base Sequence↗

PubMed1995

Co-modulation between acetylcholinesterase and cyclic nucleotide signal transduction systems in burn trauma.

Signal transduction systems (sts(s)) and acetylcholinesterase (AChE) levels in skeletal muscle distantly located from the site of large body surface area (BSA) burns are due to the systemic effects of burn trauma. Evaluating the guanylate and adenylate cyclase sts(s), by measuring adenosine 3':5'-phosphate (cyclic AMP) and guanosine 3':5'-phosphate (cyclic GMP) by radioimmunoassay with polymorphic forms of AChE demonstrated that the various systems (i.e., cyclic GMP and AChE) interact while under the duress of burn trauma. This trauma emanates from large skin burns (30-50% BSA) that have induced a chronic burn trauma response at postburn day 21. This study showed that a system, with a minimum of 2 components, regulated cyclic AMP levels. This paper provides insight into our current understanding of the effects of burn trauma on cellular signalling and discusses some of the potential implications of recent findings on long term rehabilitative care.

Acetylcholinesterase↗

PubMed1995

Localization of protein kinases by anchoring proteins: a theme in signal transduction.

A fundamental question in signal transduction is how stimulation of a specific protein kinase leads to phosphorylation of particular protein substrates throughout the cell. Recent studies indicate that specific anchoring proteins located at various sites in the cell compartmentalize the kinases to their sites of action. Inhibitors of the interactions between kinases and their anchoring proteins inhibit the functions mediated by the kinases. These data indicate that the location of these anchoring proteins provides some of the specificity of the responses mediated by each kinase and suggest that inhibitors of the interaction between the kinases and their anchoring proteins may be useful as therapeutic agents.

Animals↗

PubMedDate not supplied

Oncogene signal transduction inhibitors from medicinal plants.

Signal transduction is believed to be altered by cellular oncogenes or tumor suppressor genes during the transformation of normal cells into malignant cells. This proposition offers an attractive target for oncogene-based anticancer drug discovery from natural sources. Protein kinases encoded or modulated by oncogenes were used to prescreen the potential antitumor activity of medicinal plants. Protein-tyrosine kinase-directed fractionation and separation of the crude extracts of Polygonum cuspidatum and Koelreuteria henryi have led to the isolation of three different classes of protein-tyrosine kinase inhibitors, anthraquinone, stilbene and flavonoid. The anthraquinone inhibitor, emodin, displayed highly selective activities against src-Her-2/neu and ras-oncogenes.

Anthraquinones↗

PubMed1989

Adrenergic signal transduction in the kidney.

During signal transduction, renal adrenoceptors associate with (as in other tissues) specific members of a family of GTP-binding (G) proteins. Renal beta-adrenoceptors activate adenylate cyclase in glomeruli and distal nephrons via an interaction with the stimulatory G protein Gs. alpha 1-Adrenoceptors bind to an as yet uncharacterized G protein and activate phospholipase C to produce the putative second messengers 1,4,5-inositol trisphosphate and diacylglycerol. alpha 1-Adrenoceptors are found in most segments of the nephron where they regulate sodium reabsorption, and metabolic functions such as gluconeogenesis. Renal alpha 2-adrenoceptors which inhibit adenylate cyclase through the inhibitory G protein Gi are located mainly in the proximal convoluted tubule and the collecting ducts. Another population of alpha 2-adrenoceptors has been identified which enhances the sodium-hydrogen exchange across the luminal membrane of proximal tubules. Ongoing research is clarifying the locations and functions of these renal adrenoceptor subtypes.

Adenylyl Cyclases↗

PubMed2000

The mechanism of action of inhibitors of bacterial two-component signal transduction systems.

Two-component signal transduction systems allow bacteria to sense and respond rapidly to changes in their environment leading to specific gene activation or repression. These two-component systems are integral in the ability of pathogenic bacteria to mount and establish a successful infection within the host and, consequently, have been recognized as targets for new anti-microbial agents. In this paper, we define the site and mechanism of action of several previously identified inhibitors of bacterial two-component systems. We show that the most potent inhibitors target the carboxyl-terminal catalytic domain of the sensor kinase and exert their affect by causing structural alterations of the kinase leading to aggregation. Recognition of this phenomenon has important implications for the development of novel inhibitors of two-component systems and should facilitate the rapid identification and elimination of compounds with nonspecific affects from medicinal chemistry drug discovery programs.

Anti-Bacterial Agents↗

PubMed1997

The effect of the molecular mechanism of G protein-coupled receptor activation on the process of signal transduction.

A thermodynamic model of signal transduction that incorporates the possibility of multiple conformational states between the inactive and the active forms of the receptor was developed. The obtained equilibrium model is equivalent to the extended ternary complex of Samama et al. (J. Biol. Chem. 268 (1993) 4625-4636) if only two states of the receptor exist. These multiple equilibria between receptor states are modeled by two sets of equilibrium constants: K(piAR) and K(sigma piAR), in the presence of the ligand; and K(piR) and K(sigma piR), in the absence of the ligand. The higher the value of these constants, the more efficiently the active form of the receptor is generated. Intrinsic efficacy of the agonist is defined in the present formulation as the molecular processes induced by ligands in the receptor that lead to the active form of the receptor. Both the energetics (associated to K[piAR]) and mechanism of the process of receptor activation (associated to K[sigma piAR]) are important in eliciting the maximum response. Moreover, analytical expressions of basal activity, potency and maximum response were obtained. These definitions were used to classify the extra cellular ligand as agonists (K[sigma piAR] > K[sigma piR]), inverse agonists (K[sigma piR] > K[sigma piAR] > 0), neutral antagonists (K[sigma piAR] = K[sigma piR]), and pure antagonists.

Computer Simulation↗

PubMed1995

Characterization of the signal transduction of prostaglandin E receptor EP1 subtype in cDNA-transfected Chinese hamster ovary cells.

We examined the signal transduction of mouse prostaglandin E receptor EP1 subtype using Chinese hamster ovary cells stably expressing the cloned EP1. Sulprostone, an EP1 agonist, induced a rapid increase in intracellular Ca2+ concentration in the EP1-expressing cells. Most of the increase was abolished by removal of extracellular Ca2+, and was insensitive to U-73122, a phospholipase C inhibitor. Sulprostone stimulated phosphatidylinositol hydrolysis, but this stimulation was abolished by removal of extracellular Ca2+, indicating that EP1-stimulated phosphatidylinositol hydrolysis is the result of extracellular Ca2+ influx. Thus, the signal transduction of EP1 is extracellular Ca2+ entry through a pathway independent of phospholipase C activation. We further examined the regulation of the signal transduction of EP1 having potential phosphorylation sites for either protein kinase C or protein kinase A. Short-term exposure of the cells to 12-O-tetradecanoylphorbol 13-acetate (TPA) completely suppressed the sulprostone-induced increase in intracellular Ca2+ concentration, while forskolin or dibutyryl cAMP did not affect it, suggesting that protein kinase C but not protein kinase A is involved in the regulation of the EP1 signal transduction. Furthermore, long-term exposure to TPA decreased PGE2 protein kinase A is involved in the regulation of the EP1 signal transduction. Furthermore, long-term exposure to TPA decreased PGE2 binding activity of EP1 due to the reduction of the EP1 mRNA level. Protein kinase C induces short- and long-term desensitization of EP1.

Animals↗

PubMed2000

Signal transduction by xenobiotics in fish.

Signal transduction by xenobiotics in fish has recently gained much attention. The better known transduction mechanisms are those elicited by organochlorines, organophosphates, carbamates and heavy metals. Organochlorines specifically bind to the membrane bound ouabain sensitive Na+-K+-ATPase affecting neural transmission while the organophosphates and carbamates bind specifically to the membrane bound enzyme acetylcholinesterase again affecting neural transmission. Since the nervous system is one of the important integrative and interactive physiological systems in animals, hypofunction of the nervous system leads to secondary effects in the endocrine system including thyroidal, gonadal, interrenal, pituitary and hypothalamic functions. Even low levels of xenobiotics are efficient enough to bring about remarkable changes in the functional physiology of the non target animals. Heavy metals such as cadmium or mercury belonging to the same group II B in the periodic table probably have a similar mechanism of action. Avidity of these metals to SH-radicals allow them to bind indiscriminately to SH groups in proteins. One pathway of interaction by inorganic mercury with the membrane bound ouabain sensitive Na+-K+-ATPase has been clearly established in fish liver and ovary. Binding of inorganic mercury to the membrane bound enzyme is through sulfhydryl group which inactivates the sodium pump leading to accumulation of the cation in the cytosol. The inorganic mercury is next conjugated by the cytosolar nucleophile, glutathione, and is transported to the nucleus where dissociation occurs and the free metal binds to the metal regulatory element to initiate gene expression. The inducible proteins are 3beta-hydroxysteroid dehydrogenase in the oocyte and metallothionein and C-reactive protein in the liver. The present review deals with the role of xenobiotic as a stress factor.

Animals↗

PubMedDate not supplied

Signal transduction in gastrointestinal smooth muscle.

Signal transduction in gastric and intestinal smooth muscle is mediated by receptors coupled via distinct G proteins to various effector enzymes, including PI-specific PLC-beta 1 and PLC-beta 3, and phosphatidylcholine (PC)-specific PLC, PLD and PLA2. Activation of these enzymes is different in circular and longitudinal muscle cells, generating Ca(2+)-mobilizing (IP3, AA, cADPR) and other (DAG) messengers responsible for the initial and sustained phases of contraction, respectively. IP3-dependent Ca2+ release occurs only in circular muscle. Ca2+ mobilization in longitudinal muscle involves a cascade initiated by agonist-induced transient activation of PLA2 and formation of AA, AA-dependent depolarization of the plasma membrane and opening of voltage-sensitive Ca2+ channels. The influx of Ca2+ induces Ca2+ release by activating sarcoplasmic ryanodine receptor/Ca2+ channel and stimulates cADPR formation which enhances Ca(2+)-induced Ca2+ release. The initial [Ca2+]i transient in both muscle cell types results in Ca2+/calmodulin-dependent activation of MLC kinase, phosphorylation of MLC20 and interaction of actin and myosin. The sustained phase is mediated by a Ca(2+)-independent isoform of PKC, PKC-epsilon DAG for this process is generated by PLC- and PLD-mediated hydrolysis of PC. Relaxation is mediated by cAMP-and/or cGMP-dependent protein kinase which inhibit the initial [Ca2+]i transient and reduce the sensitivity of MLC kinase to [Ca2+]i. Relaxation induced by the main neurotransmitters, VIP and PACAP, involves two cascades, one of which reflects activation of adenylyl cyclase. A distinct cascade involves G-protein-dependent stimulation of Ca2+ influx leading to Ca2+/calmodulin-dependent activation of a constitutive eNOS in muscle cells; the generation of NO activates soluble guanylyl cyclase. The resultant activation of PKA and PKG is jointly responsible for muscle relaxation.

Animals↗

PubMed1995

Desensitization and resensitization of human platelets to 5-hydroxytryptamine at the level of signal transduction.

Desensitization of platelets to 5-hydroxytryptamine (5HT) (1 microM), during active removal of the agonist by the platelet 5HT-uptake system, was studied at the level of signal transduction. Desensitization to 5HT was dose-dependent and homologous. Without occupation of the 5HT2 receptor, neither an increase in cytosolic [Ca2+] (30 nM ionomycin), nor a separate or simultaneous activation of protein kinase C (by 10 microM 1-oleoyl-2-acetylglycerol), could induce desensitization to 5HT (1 microM). During the early phase of desensitization, the 5HT2 receptor was coupled to phospholipase C, whereas during the late phase of desensitization this coupling was disconnected. However, after disappearance of the agonist, the coupling in the resting platelet recovered quickly, and was nearly complete (82%) after 30 min. During this resensitization, the 5HT-inducibility of activation of phospholipase C, of the increase in cytosolic [Ca2+] and of stimulation of protein kinase C were restored in parallel. The time course for resensitization of the 5HT-induced increase in cytosolic [Ca2+] was independent of the presence of extracellular Ca2+. It is concluded that, after dissociation of 5HT from the platelet 5HT2-receptor, 5HT-induced responses rapidly resensitize. Because of its short duration and the parallelism in recovery between the different 'down-stream phospholipase C' intracellular transduction signals, it is considered that desensitization arises from a reversible change in the transduction mechanism at a step up to or including the activation of phospholipase C. Neither desensitization nor resensitization to 5HT is dependent on the presence of extracellular Ca2+.

Blood Platelets↗

PubMed1997

Insulin signal transduction by a mutant human insulin receptor lacking the NPEY sequence. Evidence for an alternate mitogenic signaling pathway that is independent of Shc phosphorylation.

The cytoplasmic juxtamembrane domain of the human insulin receptor (hIR) contains a single copy of the tetrameric amino acid sequence Asn-Pro-Glu-Tyr (NPEY) (residues 969-972 in the exon 11-containing B-isoform), which exists in the context of NPXY. In this study, we examined the role of NPEY972 in mediating insulin signal transduction and cellular biological effects. Transfected Chinese hamster ovary cell lines expressing either the wild-type hIR-B isoform (hIR.WT) or a mutant receptor lacking the NPEY972 sequence (hIRDeltaNPEY) and control Chinese hamster ovary.Neo cells were used to comparatively analyze the following insulin effects: in vivo receptor tyrosine autophosphorylation and kinase activity, signal transduction to downstream signaling molecules, and stimulation of glycogen and DNA synthesis. The results showed that in comparison to hIR.WT, the hIRDeltaNPEY mutant demonstrated the following: (a) normal insulin-mediated receptor tyrosine phosphorylation, but approximately 50% reduction in phosphorylation of p185-(insulin receptor substrate-1) and binding of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase), (b) an enhanced stimulation of PI 3-kinase enzymatic activity, (c) a complete inability to phosphorylate Shc, (d) minimal impairment of insulin sensitivity for glycogen synthesis, and (e) an augmented response to insulin-stimulated DNA synthesis via a high capacity, low sensitivity pathway. These results demonstrate the following: 1) the NPEY972 sequence is important but not absolutely essential for coupling of hIR kinase to insulin receptor substrate-1 and p85 or for mediating insulin's metabolic and mitogenic effects, 2) the NPEY972 sequence is necessary for Shc phosphorylation, and 3) the absence of Shc phosphorylation releases the constraints on maximal insulin-stimulated mitogenic response, thus indicating that alternate signaling pathway(s) exist for this insulin action. This alternate pathway appears to be associated with enhanced activation of PI 3-kinase and is of high capacity and low sensitivity.

Animals↗

PubMed1998

Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics.

Delayed effects for pharmacodynamic responses can be observed for many signal transduction processes. Three approaches are summarized in this report to describe such effects caused by cascading steps: stochastic process model, gamma distribution function, and transit compartment model. The gamma distribution function, a probability density function of the waiting time for the final step in a stochastic process model, is a function of time with two variables: number of compartments N, and the expected number of compartments occurring per unit time k. The parameter k is equal to 1/tau, where tau is the mean transit time in the stochastic process model. Effects of N and k on the gamma distribution function were examined. The transit compartment model can link the pharmacokinetic profile of the tested compound, receptor occupancy, and cascade steps for the signal transduction process. Time delays are described by numbers of steps, the mean transit time tau, and the amplification or suppression of the process as characterized by a power coefficient gamma. The effects of N, tau, and gamma on signal transduction profiles are shown. The gamma distribution function can be utilized to estimate N and k values when the final response profile is available, but it is less flexible than transit compartments when dose-response relationships, receptor dynamics, and efficiency of the transduction process are of concern. The transit compartment model is useful in pharmacokinetic/pharmacodynamic modeling to describe precursor/product relationships in signal transduction process.

Animals↗

PubMed1999

Stimulation of pancreatic beta-cell proliferation by growth hormone is glucose-dependent: signal transduction via janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mitogenic signalling.

Mitogenic signal-transduction pathways have not been well defined in pancreatic beta-cells. In the glucose-sensitive rat beta-cell line, INS-1, glucose (6-18 mM) increased INS-1 cell proliferation (>20-fold at 15 mM glucose). Rat growth hormone (rGH) also induced INS-1 cell proliferation, but this was glucose-dependent in the physiologically relevant concentration range (6-18 mM glucose). The combination of rGH (10 nM) and glucose (15 mM) was synergistic, maximally increasing INS-1 cell proliferation by >50-fold. Moreover, glucose-dependent rGH-induced INS-1 cell proliferation was increased further by addition of insulin-like growth factor 1 (IGF-1; 10 nM) to >90-fold at 12 mM glucose. Glucose metabolism and phosphatidylinositol-3'-kinase (PI3'K) activation were necessary for both glucose- and rGH-stimulated INS-1 cell proliferation. Glucose (>3 mM) independently increased tyrosine-phosphorylation-mediated recruitment of growth-factor-bound protein 2 (Grb2)/murine sons of sevenless-1 protein (mSOS) and PI3'K to insulin receptor substrate (IRS)-1 and IRS-2, as well as SH2-containing protein (Shc) association with Grb2/mSOS and downstream activation of mitogen-activated protein kinase and 70 kDa S6 kinase. Glucose-induced IRS- and Shc-mediated signal transduction was enhanced further by the addition of IGF-1, but not rGH. In contrast, rGH was able to activate Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signal transduction at glucose concentrations above 3 mM, but neither glucose independently, nor glucose with added IGF-1, were able to activate the JAK2/STAT5 signalling pathway. Thus rGH-mediated proliferation of beta-cells is directly via the JAK2/STAT5 pathway without engaging the Shc or IRS signal-transduction pathways, although activation of PI3'K may play an important permissive role in the glucose-dependent aspect of rGH-induced beta-cell mitogensis. The additive effect of rGH and IGF-1 on glucose-dependent beta-cell proliferation is therefore reflective of rGH and IGF-1 activating distinctly different mitogenic signalling pathways in beta-cells with minimal crosstalk between them.

Adaptor Proteins, Signal Transducing↗

PubMed1996

AKR1 encodes a candidate effector of the G beta gamma complex in the Saccharomyces cerevisiae pheromone response pathway and contributes to control of both cell shape and signal transduction.

Mating pheromones of Saccharomyces cerevisiae control both signal transduction events and changes in cell shape. The G beta gamma complex of the pheromone receptor-coupled G protein activates the signal transduction pathway, leading to transcriptional induction and cell cycle arrest, but how pheromone-dependent signalling leads to cell shape changes is unclear. We used a two-hybrid system to search for proteins that interact with the G beta gamma complex and that might be involved in cell shape changes. We identified the ankyrin repeat-containing protein Akr1p and show here that it interacts with the free G beta gamma complex. This interaction may be regulated by pheromone, since Akr1p is excluded from the G alpha beta gamma heterotrimer. Both haploid and diploid cells lacking Akr1p grow slowly and develop deformed buds or projections, suggesting that this protein participates in the control of cell shape. In addition, Akr1p has a negative influence on the pheromone response pathway. Epistasis analysis demonstrates that this negative effect does not act on the G beta gamma complex but instead affects the kinase cascade downstream of G beta gamma, so that the kinase Ste20p and components downstream of Ste20p (e.g., Ste11p and Ste7p) are partially activated in cells lacking Akr1p. Although the elevated signalling is eliminated by deletion of Ste20p (or components downstream of Ste20p), the growth and morphological abnormalities of cells lacking Akr1p are not rescued by deletion of any of the known pheromone response pathway components. We therefore propose that Akr1p negatively affects the activity of a protein that both controls cell shape and contributes to the pheromone response pathway upstream of Ste20p but downstream of G beta gamma. Specifically, because recent evidence suggests that Bem1p, Cdc24p, and Cdc42p can act in the pheromone response pathway, we suggest that Akr1p affects the functions of these proteins, by preventing them from activating mating-specific targets including the pheromone-responsive kinase cascade, until G beta gamma is activated by pheromone.

Base Sequence↗

PubMed1997

T cell antigen receptor signal transduction.

The T cell antigen receptor (TCR) initiates signal transduction by activating multiple cytoplasmic protein tyrosine kinases (PTKs). Considerable progress in the field of TCR signal transduction has been made in three areas recently: first, in understanding the structure and function of the PTK ZAP-70; second, in the elucidation of the function of the substrates and pathways downstream of the PTKs; and third, in the identification of molecules that negatively regulate TCR signalling.

Animals↗