Biomedical subjects

H B Peng

Publications and source records attributed to H B Peng.

At least 37 records · Page 2Linked to original sources

PubMed1997

Association of cortactin with developing neuromuscular specializations.

During the development of the neuromuscular junction (NMJ), motoneurons grow to the muscle cell and the nerve-muscle contact triggers the development of both presynaptic specialization, consisting of clusters of synaptic vesicles (SVs), and postsynaptic specialization, consisting of clusters of synaptic vesicles (SVs), and postsynaptic specialization, consisting of clusters of acetylcholine receptors (AChRs). Previous studies have shown that the activation of tyrosine kinases and the local assembly of an actin-based cytoskeletal specialization are involved in the development of both types of specializations. To understand the link between tyrosine phosphorylation and the assembly of the cytoskeleton, we examined the localization of cortactin in relationship to synaptic development. Cortactin is a 80/85 kD F-actin binding protein and is a substrate for tyrosine kinases. It contains a proline-rich motif and an SH3 domain and is localized at sites of active F-actin assembly. Using a monoclonal antibody against cortactin, its localization at developing NMJs in culture was observed. To understand the spatial and temporal relationship between cortactin and developing synaptic structures, cultured muscle cells and spinal neurons from Xenopus embryos were treated with beads coated with heparin-binding growth-associated molecule to induce the formation of AChR clusters and SV clusters and the localization of cortactin was followed by immunofluorescence. In untreated muscle cells, cortactin is often co-localized with spontaneously formed AChR clusters. After cells were treated with beads, cortactin became localized at bead-induced AChR clusters at their earliest appearance (1 h after the addition of beads). This association was most reliably detected at the early stage of the clustering process. On the presynaptic side, cortactin localization could be detected as early as 10 min after the bead-neurite contact was established. Cortactin-enriched contacts later showed concentration of F-actin (at 1 h) and clusters of SVs (at 24 h). These data suggest that cortactin mediates the local assembly of the cytoskeletal specialization triggered by the synaptogenic signal on both nerve and muscle.

Actins↗

PubMed1996

Nitric oxide attenuates vascular smooth muscle cell activation by interferon-gamma. The role of constitutive NF-kappa B activity.

Atherogenesis involves cellular immune responses and altered vascular smooth muscle cell (SMC) function. Cytokines such as interleukin (IL)-1 alpha and interferon-gamma (IFN-gamma) may contribute to this process by activating SMC. To determine whether the anti-atherogenic mediator, nitric oxide (.NO), can modulate cytokine-induced SMC activation, we investigated the effects of various .NO-generating compounds on the expression of intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). Induction of ICAM-1 expression by IL-1 alpha and VCAM-1 expression by IFN-gamma was attenuated by .NO donors but not by cGMP analogues. Nuclear run-on assays and transfection studies using various VCAM-1 promoter constructs linked to the chloramphenicol acetyl-transferase reporter gene showed that .NO repressed IFN-gamma-induced VCAM-1 gene transcription, in part, through inhibition of nuclear factor-kappa B (NF-kappa B). Electrophoretic mobility shift assay revealed that SMC possess basal constitutive NF-kappa B activity, which was augmented by treatment with IL-1 alpha. In contrast, IFN-gamma induced and activated interferon regulatory factor (IRF)-1 but had little effect on basal constitutive NF-kappa B activity. .NO donors had no inhibitory effect on IRF-1 activation but did inhibit basal and IL-1 alpha-stimulated NF-kappa B activation. These findings suggest that the induction of ICAM-1 and VCAM-1 expression requires NF-kappa B activation and that .NO attenuates IFN-gamma-induced VCAM-1 expression primarily by inhibiting basal constitutive NF-kappa B activity in SMC.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1996

Association of phosphotyrosine with rapsyn expression in Xenopus embryonic cells.

The postsynaptic membrane of the neuromuscular junction is highly enriched in rapsyn, which is thought to interact directly with nicotinic acetylcholine receptors (AChR) and anchor them at the synapse. We expressed rapsyn with or without AChRs in Xenopus embryos by mRNA injection. Co-expression of AChR and rapsyn caused the clustering of these two proteins in cultured cells isolated from the injected embryos. When rapsyn was expressed alone, it also became clustered at the substratum-facing membrane in cultured cells and at cell-cell contacts in whole mount embryos. No clusters were observed in cells that expressed AChRs alone. In rapsyn-expressing cells, proteins that are tyrosine phosphorylated as shown by anti-phosphotyrosine antibody labeling were concentrated at rapsyn clusters. Rapsyn itself does not appear to be a substrate for tyrosine kinase. This suggests that other phosphotyrosine-containing proteins are co-clustered with rapsyn in these cells.

Animals↗

PubMed1996

Full-length agrin isoform activities and binding site distributions on cultured Xenopus muscle cells.

Agrin is a large multidomain protein involved in the induction of postsynaptic differentiation of the neuromuscular junction. As a step toward further understanding the mechanisms by which agrin induces the aggregation of acetylcholine receptors (AChRs), we have characterized the activity of purified, full-length chick agrin isoforms on Xenopus muscle cells. Incubation with agrin isoforms led to the formation of numerous small AChR clusters primarily on the ventral surface of cells with differing efficacies: Y4Z8 > Y4Z11 = Y4Z19, with Y4B0 being ineffective. Agrin activity appeared to be tyrosine phosphorylation-dependent as the kinase inhibitor tyrphostin RG50864 (80 microM) completely abolished the effect. Initial binding sites for all agrin isoforms were evenly distributed in a punctate manner on the muscle cell surface. After a 14-h incubation, the active isoforms induced AChR clustering, and agrin was enriched at these sites of clustering. Agrin binding to the cell surface and induction of AChR clustering were Ca(2+)-dependent, as previously shown in other systems. This is the first quantitative characterization of agrin's effects using Xenopus cell culture, providing a basis for further elucidating agrin's role in synaptogenesis using this elegant system.

Agrin↗

PubMed1996

Dynamics of synaptic vesicles in cultured spinal cord neurons in relationship to synaptogenesis.

The dynamics of synaptic vesicles (SVs) during the development of presynaptic specializations in cultured Xenopus spinal cord neurons was studied with the fluorescent vesicular probe FM1-43. In naive neurons that have not contacted synaptic targets, packets of SVs are distributed along the entire neurite and are quite mobile. The interaction with the synaptic target, such as a muscle cell or a latex bead coated with basic fibroblast growth factor, results in the localization and immobilization of SV packets at the contact site. Depolarization resulted in exocytosis of SVs in both naive and target-contacted neurites. Okadaic acid, a phosphatase inhibitor, caused a dispersal of SV packets in both naive and target-contacted neurites. Thus, prior to target contact, SVs are already organized into packets capable of release and recycling by a phosphorylation-dependent mechanism. Target interaction then recruits and anchors these functional SV packets into forming the presynaptic nerve terminal. With fluorescent phalloidin as a probe, F-actin was found to colocalize with SV clusters at bead-neurite contacts. Although okadaic acid caused a dispersal of SVs at the beads, F-actin localization there was relatively resistant to this drug treatment. This suggests that SVs become localized at the target by interacting with an actin-based cytoskeletal specialization in a phosphorylation-sensitive manner. The induction of this cytoskeletal specialization by the target may be an early event in presynaptic differentiation.

Actins↗

PubMed1996

The role of an agrin-growth factor interaction in ACh receptor clustering.

The clustering of acetylcholine receptors (AChRs) at the neuromuscular junction is mediated in part by the heparan-sulfate proteoglycan agrin. However, our previous studies have also suggested the role of heparin-binding growth-associated molecular (HB-GAM) in AChR clustering. Here the role of an agrin-HB-GAM interaction in this process was examined using cultured Xenopus muscle cells. Agrin-coated beads further treated with HB-GAM were highly effective in AChR cluster induction. Protein overlay assays showed specific binding of HB-GAM to agrin. In addition, agrin-enriched neuritic tracks bound HB-GAM in a manner that showed a high degree of colocalization between the neural agrin and the applied factor. Finally, the introduction of exogenous HB-GAM together with soluble agrin resulted in the appearance of AChR clusters on the dorsal surface of cells in an agrin isoform-dependent manner; a dramatic change from the characteristic ventral AChR clustering seen in response to agrin alone. These results suggest that agrin may mediate AChR clustering by interacting with muscle-bound heparin-binding growth factors such as HB-GAM.

Agrin↗

PubMed1995

Nitric oxide inhibits macrophage-colony stimulating factor gene transcription in vascular endothelial cells.

Macrophage-colony stimulating factor (M-CSF) contributes to atherogenesis by regulating macrophage-derived foam cells in atherosclerotic lesions. Here we report that nitric oxide (NO) inhibits the expression of M-CSF in human vascular endothelial cells independent of guanylyl cyclase activation. The induction of M-CSF mRNA expression by either oxidized low density lipoprotein (ox-LDL) or tumor necrosis factor-alpha (TNF alpha) was attenuated by NO donors, S-nitrosoglutathione (GSNO), sodium nitroprusside (SNP), and 3-morpholinosydnonimine, but not by cGMP analogues, glutathione, or nitrite. Inhibition of endogenous NO production by N-monomethyl-L-arginine (L-NMA) also increased M-CSF expression in control and TNF alpha-stimulated cells. Nuclear run-on assays and transfection studies using M-CSF promoter constructs linked to chloramphenicol acetyltransferase reporter gene indicated that NO repressed M-CSF gene transcription through nuclear factor-kappa B (NF-kappa B). Electrophoretic mobility shift assays demonstrated that activation of NF-kappa B by L-NMA, ox-LDL, and TNF alpha was attenuated by GSNO and SNP, but not by glutathione or cGMP analogues. Since the induction of M-CSF expression depends upon NF-kappa B activation, the ability of NO to inhibit NF-kappa B activation and M-CSF expression may contribute to some of NO's antiatherogenic properties.

Base Sequence↗

PubMed1995

Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B.

To determine the mechanism(s) by which the endogenous mediator nitric oxide (NO) inhibits the activation of transcription factor NF-kappa B, we stimulated human vascular endothelial cells with tumor necrosis factor-alpha in the presence of two NO donors, sodium nitroprusside and S-nitrosoglutathione. Electrophoretic mobility shift assays demonstrated that both NO donors inhibited NF-kappa B activation by tumor necrosis factor-alpha. This effect was not mediated by guanylyl cyclase activation since the cGMP analogue 8-bromo-cGMP had no similar effect. Inhibition of endogenous constitutive NO production by L-N-monomethylarginine, however, activated NF-kappa B, suggesting tonic inhibition of NF-kappa B under basal conditions. NO had little or no effects on other nuclear binding proteins such as AP-1 and GATA. Immunoprecipitation studies showed that NO stabilized the NF-kappa B inhibitor, I kappa B alpha, by preventing its degradation from NF-kappa B. NO also increased the mRNA expression of I kappa B alpha, but not NF-kappa B subunits, p65 or p50, and transfection experiments with a chloramphenicol acetyltransferase reporter gene linked to the I kappa B alpha promoter suggested transcriptional induction of I kappa B alpha by NO. We propose that the induction and stabilization of I kappa B alpha by NO are important mechanisms by which NO inhibits NF-kappa B and attenuate atherogenesis.

Base Sequence↗

PubMed1995

Induction of acetylcholine receptor cluster formation by local application of growth factors in cultured Xenopus muscle cells.

A survey of several growth factors was carried out to determine their effect on the formation of acetylcholine receptor (AChR) clusters in cultured Xenopus muscle cells. Factors were locally applied via polystyrene beads and AChR clustering at bead-muscle contacts was assessed. Among the factors tested, basic fibroblast growth factor, insulin and insulin-like growth factor-I, as well as several polycations, were found to be effective in inducing AChR clusters. The action of these molecules appears to be mediated by tyrosine kinase receptors, since it can be blocked by a tyrosine kinase inhibitor. These results suggest that local ligand-mediated tyrosine phosphorylation is involved in the formation of AChR clusters.

Animals↗

PubMed1995

Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.

To test the hypothesis that nitric oxide (NO) limits endothelial activation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the inducible expression of vascular cell adhesion molecule-1 (VCAM-1). In a concentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-stimulated VCAM-1 expression by 35-55% as determined by cell surface enzyme immunoassays and flow cytometry. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers in nonstatic assays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosis factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and to a lesser extent, intercellular adhesion molecule-1) and secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO production by L-N-monomethyl-arginine also induced the expression of VCAM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter reporter gene constructs, and electrophoretic mobility shift assays indicated that NO represses VCAM-1 gene transcription, in part, by inhibiting NF-kappa B. We propose that NO's ability to limit endothelial activation and inhibit monocyte adhesion may contribute to some of its antiatherogenic and antiinflammatory properties within the vessel wall.

Base Sequence↗

PubMed1995

Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen.

Oxygen (O2) may regulate pulmonary vascular resistance through changes in endothelial nitric oxide (NO) production. To determine whether constitutive NO synthase (cNOS) is regulated by O2, we assessed cNOS expression and activity in bovine pulmonary artery endothelial cells exposed to different concentrations of O2. In a time-dependent manner, changes in O2 concentration from 95 to 3% produced a progressive decrease in cNOS mRNA and protein levels resulting in 4.8- and 4.3-fold reductions after 24h, respectively. This correlated with changes in cNOS activity as determined by nitrite measurements. Compared with 20% O2, cNOS activity was increased 1.5-fold in 95% O2 and decreased 1.9-fold in 3% O2. A decrease in O2 concentration from 94 to 3% shortened cNOS mRNA half-life from 46 to 24 h and caused a 20-fold repression of cNOS gene transcription. Treatment with cycloheximide produced a threefold increase in cNOS mRNA at all O2 concentrations, suggesting that cNOS mRNA expression is negatively regulated under basal condition. We conclude that O2 upregulates cNOS expression through transcriptional and post-transcriptional mechanisms. A decrease in cNOS activity in the presence of low O2 levels, therefore, may contribute to hypoxia-induced vasoconstriction in the pulmonary circulation.

Aerobiosis↗

PubMed1995

Presynaptic differentiation induced in cultured neurons by local application of basic fibroblast growth factor.

Recent studies have suggested a role for molecules residing at the muscle surface in signaling presynaptic development at the neuromuscular junction (NMJ). Since heparan sulfate-proteoglycan is a major component of the extracellular matrix of skeletal muscle, factors that are bound to this proteoglycan, such as basic fibroblast growth factor (bFGF), are in a strategic position for neuronal signaling. To test this idea, we applied bFGF to cultured Xenopus spinal cord neurons and monitored the change in intracellular Ca2+ level with fura-2 ratio imaging. In one-third of the neurons, local application of bFGF elicited a 30-140% increase in intracellular Ca2+ level. Ca(2+)-free medium or suramin abolished this change. Latex beads coated with bFGF induced clustering of synaptic vesicles at the bead-neurite contacts as evidenced by anti-synaptotagmin antibody labeling and electron microscopy. This response was also blocked by Ca(2+)-free medium and by suramin. Uncoated beads or beads coated with PDGF were ineffective. This induction was also inhibited by a tyrosine kinase inhibitor, tyrphostin RG-50864, suggesting the role of receptor tyrosine kinase activation in this process. In addition, bFGF-coated beads also induced the localization of depolarization-dependent Ca2+ influx to the bead-neurite contacts. In contrast, depolarization caused a distributed Ca2+ elevation in untreated neurites. These results suggest that local presentation of bFGF can mimic the muscle target in signaling the development of both a cytoplasmic and a membranous specialization for excitation-secretion coupling observed at the NMJ.

Animals↗

PubMed1995

The role of heparin-binding growth-associated molecule (HB-GAM) in the postsynaptic induction in cultured muscle cells.

The heparan sulfate proteoglycan (HSPGs) is a components of the extracellular matrix of skeletal muscle that is concentrated at the neuromuscular junction (NMJ). Recent studies have suggested that HSPG, together with its bound peptide growth factors, plays important roles in autocrine or paracrine types of regulation of cell growth and differentiation. Heparin-binding growth-associated molecule (HB-GAM; also known as pleiotrophin, or p18) is a newly discovered HSPG-bound factor that is expressed at high levels in the developing CNS and PNS. In this study, we examined the role of this factor in NMJ development by examining its relationship to the formation of ACh receptor (AChR) clusters. Using an antibody against recombinant rat brain HB-GAM, we found that this protein is present prominently on the surface of cultured Xenopus myotomal muscle cells by immunocytochemistry. It is associated with HSPGs as evidenced by the fact that heparin and heparinase treatment greatly diminished the antibody labeling. HB-GAM is concentrated at preexisting AChR hot spots as well as at those induced by polystyrene beads. In addition, this molecule is also concentrated at AChR clusters induced by spinal cord neurons in nerve-muscle cocultures. To assess its function in synaptic induction, we applied recombinant HB-GAM-coated beads to cultured muscle cells to effect its focal presentation. Over 70% of these beads induced the formation of AChR clusters as shown by fluorescent alpha-bungarotoxin labeling. Furthermore, bath application of HB-GAM inhibited the nerve-induced formation of AChR clusters. Thus, HB-GAM is an endogenous muscle-derived factor that may be a component of the molecular mechanism in postsynaptic induction.

Animals↗

PubMed1994

Concentration of pp125 focal adhesion kinase (FAK) at the myotendinous junction.

Focal adhesion kinase is a recently characterized tyrosine kinase that is concentrated at focal contacts in cultured cells. It is thought to play an important role in the regulation of the integrin-based signal transduction mechanism involved in the assembly of this membrane specialization. In this study, we examined the immunocytochemical distribution of focal adhesion kinase in Xenopus skeletal muscle and its role in the formation of two sarcolemmal specializations, the myotendinous junction and the neuromuscular junction, using a monoclonal antibody (2A7) against this protein. Immunoprecipitation of Xenopus embryonic tissues with this antibody demonstrated a single band at a relative molecular mass of 116 kDa. A distinct concentration of immunolabeling for focal adhesion kinase was observed at the myotendinous junction of muscle fibers in vivo. At this site, the labeling for this protein is correlated with an accumulation of phosphotyrosine immunolabeling. Focal adhesion kinase was not concentrated at the neuromuscular junction in muscle cells either in vivo or in vitro. However, it was localized at spontaneously formed acetylcholine receptor clusters in cultured Xenopus myotomal muscle cells, although its distribution was not exactly congruent with that of the receptors. In these cells, the accumulation focal adhesion kinase was induced by polystyrene microbeads. In addition, beads also induce the formation of acetylcholine receptor clusters and myotendinous junction-like specializations. By following the appearance of the focal adhesion kinase relative to the formation of these sarcolemmal specializations at bead-muscle contacts in cultured muscle cells, we conclude that the accumulation of this protein was in pace with the development of the myotendinous junction, but occurred well after the clustering of acetylcholine receptors. These results suggest that focal adhesion kinase may be involved in the development and/or maintenance of the myotendinous junction through an integrin-based signaling system. Although it can accumulate at acetylcholine receptor clusters formed in culture, it does not appear to be involved in the development of the neuromuscular junction.

Animals↗

PubMed1993

Elevation in presynaptic Ca2+ level accompanying initial nerve-muscle contact in tissue culture.

Nerve-muscle cocultures were used to study the relationship between neuronal Ca2+ level and the earliest nerve-muscle interaction. Xenopus spinal cord neurons were loaded with Ca2+ indicators and monitored by digital video microscopy as a myoball was manipulated into contact with it. Transmitter release was measured from the myoball by whole-cell recording. We observed a 1.5- to 6-fold increase in Ca2+ level in the neurite upon contact with a myoball. Fifty percent of the pairs showing Ca2+ elevation were also positive for neurotransmission. This Ca2+ rise was suppressed by lifting away the myoball, by Ca(2+)-free solution, or by suramin, a polyanionic compound that interferes with cell surface receptors. This suppression was accompanied by a reduction in transmitter release. The specificity of the nerve-muscle contact-induced Ca2+ rise was shown by its absence upon neuron-neuron contact. Naturally formed nerve-muscle contacts also showed an elevation in presynaptic Ca2+ level. Thus, this elevation appears to be a physiological step in the early stage of synaptogenesis and is likely mediated by muscle-derived molecules.

Animals↗

PubMed1993

Comparison of infrared electronic endoscopy using reflection and transmission.

Twelve subjects were examined using both the reflecting type of infrared electronic endoscopy and the transmission method to visualize submucosal gastric architecture. Under transmission infrared illumination, submucosal structures were more clearly observed than by using the reflecting type. Using the transmission method, only the anterior wall of the antrum could be fully visualized, although the anterior wall of the lower corpus was recognized in only 33% of the cases. Furthermore, the upper or middle corpus and the entire posterior wall were not properly recognized using transmission illumination. The entire gastric circumference was visualized with the reflecting type illumination. Both types of infrared illumination of the gastric wall can be used complementarily for visualizing submucosal gastric architecture.

Aged↗

PubMed1993

Tyrosine phosphorylation and acetylcholine receptor cluster formation in cultured Xenopus muscle cells.

Aggregation of the nicotinic acetylcholine receptor (AChR) at sites of nerve-muscle contact is one of the earliest events to occur during the development of the neuromuscular junction. The stimulus presented to the muscle by nerve and the mechanisms underlying postsynaptic differentiation are not known. The purpose of this study was to examine the distribution of phosphotyrosine (PY)-containing proteins in cultured Xenopus muscle cells in response to AChR clustering stimuli. Results demonstrated a distinct accumulation of PY at AChR clusters induced by several stimuli, including nerve, the culture substratum, and polystyrene microbeads. AChR microclusters formed by external cross-linking did not show PY colocalization, implying that the accumulation of PY in response to clustering stimuli was not due to the aggregation of basally phosphorylated AChRs. A semi-quantitative determination of the time course for development of PY labeling at bead contacts revealed early PY accumulation within 15 min of contact before significant AChR aggregation. At later stages (within 15 h), the AChR signal came to approximate the PY signal. We have reported the inhibition of bead-induced AChR clustering in response to beads by a tyrphostin tyrosine kinase inhibitor (RG50864) (Peng, H. B., L. P. Baker, and Q. Chen. 1991. Neuron. 6:237-246). RG50864 also inhibited PY accumulation at bead contacts, providing evidence for tyrosine kinase activation in response to the bead stimulus. These results suggest that tyrosine phosphorylation may play an important role in the generative stages of cluster formation, and may involve protein(s) other than or in addition to AChRs.

Animals↗

PubMed1993

A role of tyrosine phosphorylation in the formation of acetylcholine receptor clusters induced by electric fields in cultured Xenopus muscle cells.

During the development of the neuromuscular junction, acetylcholine receptors (AChRs) become clustered in the postsynaptic membrane in response to innervation. In vitro, several non-neuronal stimuli can also induce the formation of AChR clusters. DC electric field (E field) is one of them. When cultured Xenopus muscle cells are exposed to an E field of 5-10 V/cm, AChRs become clustered along the cathode-facing edge of the cells within 2 h. Recent studies have suggested the involvement of tyrosine kinase activation in the action of several AChR clustering stimuli, including nerve, polymer beads, and agrin. We thus examined the role of tyrosine phosphorylation in E field-induced AChR clustering. An antibody against phosphotyrosine (PY) was used to examine the localization of PY-containing proteins in E field-treated muscle cells. We found that anti-PY staining was colocalized with AChR clusters along the cathodal edge of the cells. In fact, cathodal PY staining could be detected before the first appearance of AChR clusters. When cultures were subjected to E fields in the presence of a tyrosine kinase inhibitor, tyrphostin RG-50864, cathodal AChR clustering was abolished with a half maximal inhibitory dosage of 50 microM. An inactive form of tyrphostin (RG-50862) had no effect on the field-induced clustering. These data suggest that the activation of tyrosine kinases is an essential step in E field-induced AChR clustering. Thus, the actions of several disparate stimuli for AChR clustering seem to converge to a common signal transduction mechanism based on tyrosine phosphorylation at the molecular level.

Animals↗