scholarly journals IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases.

1994 ◽  
Vol 180 (6) ◽  
pp. 2101-2111 ◽  
Author(s):  
S Sato ◽  
T Katagiri ◽  
S Takaki ◽  
Y Kikuchi ◽  
Y Hitoshi ◽  
...  
Keyword(s):  
Signal Transduction ◽  
B Cell ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Catalytic Domain ◽  
Critical Role ◽  
Phosphatidyl Inositol ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Interleukin 5

Interleukin 5 (IL-5) induces proliferation and differentiation of B cells and eosinophils by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, alpha and beta (beta c). Although both IL-5R alpha and beta c lack a kinase catalytic domain, IL-5 is capable of inducing tyrosine phosphorylation of cellular proteins. We investigated the role of IL-5R alpha in tyrosine phosphorylation of molecules involved in IL-5 signal transduction, using an IL-5-dependent early B cell line, Y16 and transfectants expressing intact or mutant IL-5R alpha together with intact beta c. The results revealed that the transfectants expressing truncated IL-5R alpha, which entirely lacks a cytoplasmic domain, together with beta c, showed neither protein-tyrosine phosphorylation nor proliferation in response to IL-5. This confirms that IL-5R alpha plays a critical role in protein-tyrosine phosphorylation which triggers cell growth. IL-5 stimulation results in rapid tyrosine phosphorylation of beta c and proteins containing Src homology 2 (SH2) and/or SH3 domains such as phosphatidyl-inositol-3 kinase, Shc, Vav, and HS1, suggesting their involvement in IL-5-mediated signal transduction. IL-5 stimulation significantly enhanced activities of Janus 2 and B cell-specific Bruton's tyrosine kinases (JAK2 and Btk) and increased the tyrosine phosphorylation of JAK2 kinase. These results and recent data on signaling of growth factors taken together, multiple biochemical pathways driven by tyrosine kinases such as JAK2 and Btk are involved in IL-5 signal transduction.

scholarly journals The B cell antigen receptor of class IgD induces a stronger and more prolonged protein tyrosine phosphorylation than that of class IgM.

1995 ◽  
Vol 181 (3) ◽  
pp. 1005-1014 ◽  
Author(s):  
K M Kim ◽  
M Reth
Keyword(s):  
B Cell ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Antigen Receptor ◽  
Cross Linking ◽  
Protein Tyrosine Phosphorylation ◽  
Antigen Receptors ◽  
Antigen Specificity ◽  
Protein Tyrosine ◽  
Substrate Phosphorylation

Most mature B lymphocytes coexpress two classes of antigen receptor, immunoglobulin (Ig)M and IgD. The differences in the signal transduction from the two receptors are still a matter of controversy. We have analyzed B cell lines expressing IgM or IgD antigen receptors with the same antigen specificity. Cross-linking of these receptors with either antigen, or class-specific antibodies, results in the activation of protein tyrosine kinases and the phosphorylation of the same substrate proteins. The kinetic and the intensity of phosphorylation, however, was quite different between the two receptors when they were cross-linked by antigen. In membrane IgM-expressing cells, the substrate phosphorylation reached a maximum after 1 minute and diminished after 60 minutes whereas, in the membrane IgD-expressing cells, the substrate phosphorylation increased further over time, reached its maximum at 60 minutes, and persisted longer than 240 minutes after exposure to antigen. As a result, the intensity of protein tyrosine phosphorylation induced by cross-linking of membrane IgD was stronger than that induced by membrane IgM. Studies of chimeric receptors demonstrate that only the membrane-proximal C domain and/or the transmembrane part of membrane-bound IgD molecule is required for the long-lasting substrate phosphorylation. Together, these data suggest that the signal emission from the two receptors is controlled differently.

scholarly journals Recent advances in PTP1B signaling in metabolism and cancer

2021 ◽  
Author(s):  
Olga Villamar-Cruz ◽  
Marco A. Loza-Mejía ◽  
Luis E. Arias-Romero ◽  
Ignacio Camacho-Arroyo
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Phosphorylation ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Critical Role ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Promising Therapeutic Target ◽  
Molecular Aspects

Protein tyrosine phosphorylation is one of the major post-translational modifications in eukaryotic cells and represents a critical regulatory mechanism of a wide variety of signaling pathways. Aberrant protein tyrosine phosphorylation has been linked to various diseases, including metabolic disorders and cancer. Few years ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors, able to block the signals emanated from receptor tyrosine kinases. However, recent evidence demonstrates that a misregulation of PTPs activity plays a critical role in cancer development and progression. Here, we will focus on PTP1B, an enzyme that has been linked to the development of type 2 diabetes and obesity through the regulation of insulin and leptin signaling, and with a promoting role in the development of different types of cancer through the activation of several pro-survival signaling pathways. In this review, we discuss the molecular aspects that support the crucial role of PTP1B in different cellular processes underlying diabetes, obesity and cancer progression, and its visualization as a promising therapeutic target.

scholarly journals Internalization of the granulocyte-macrophage colony-stimulating factor receptor is not required for induction of protein tyrosine phosphorylation in human myeloid cells

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 1928-1935 ◽  
Author(s):  
K Okuda ◽  
B Druker ◽  
Y Kanakura ◽  
M Koenigsmann ◽  
JD Griffin
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Receptor Internalization ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) exerts its biologic activities through binding to specific high-affinity cell surface receptors. After binding, the ligand/receptor complex is rapidly internalized in most hematopoietic cells. Using a human factor- dependent cell line, MO7, and normal human neutrophils, we found that the internalization is exquisitely temperature-dependent, such that ligand/receptor internalization does not detectably occur at 4 degrees C. Activation of the GM-CSF receptor has previously been shown to stimulate a number of postreceptor signal transduction pathways, including activation of a tyrosine kinase and activation of the serine/threonine kinase, Raf-1. The GM-CSF-stimulated increase in tyrosine kinase activity occurs rapidly at both 4 degrees C and 37 degrees C, and therefore is likely to be independent of receptor internalization. At 37 degrees C, the protein tyrosine phosphorylation was transient in MO7 cells, with maximum phosphorylation observed after 5 to 15 minutes, followed by a rapid decline. At 4 degrees C, the protein tyrosine phosphorylation of the same substrates was greater than at 37 degrees C, and no decline in substrate phosphorylation was observed for at least 90 minutes. In contrast to tyrosine phosphorylation, the activation and hyper-phosphorylation of Raf-1 observed at 37 degrees C in both MO7 cells and neutrophils was markedly diminished at 4 degrees C. These results indicate that at least one postreceptor signal transduction mechanism, activation of a tyrosine kinase, does not require ligand/receptor internalization, and indicate that receptor internalization may be a consequence, rather than the initiator, of signal transduction.

scholarly journals Constitutive secretion of serum albumin requires reversible protein tyrosine phosphorylation events in trans-Golgi

2005 ◽  
Vol 289 (3) ◽  
pp. C748-C756 ◽  
Author(s):  
Rachel J. Webb ◽  
Jacob D. Judah ◽  
Lee-Chiang Lo ◽  
Geraint M. H. Thomas
Keyword(s):  
Serum Albumin ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Phosphorylation ◽  
Albumin Secretion ◽  
Protein Tyrosine ◽  
Constitutive Secretion

Serum albumin secretion from rat hepatocytes proceeds via the constitutive pathway. Although much is known about the role of protein tyrosine phosphorylation in regulated secretion, nothing is known about its function in the constitutive process. Here we show that albumin secretion is inhibited by the tyrosine kinase inhibitor genistein but relatively insensitive to subtype-selective inhibitors or treatments. Secretion is also blocked in a physiologically identical manner by the tyrosine phosphatase inhibitors pervanadate and bisperoxo(1,10-phenanthroline)-oxovanadate. Inhibition of either the kinase(s) or phosphatase(s) leads to the accumulation of albumin between the trans-Golgi and the plasma membrane, whereas the immediate precursor proalbumin builds up in a proximal compartment. The trans-Golgi marker TGN38 is rapidly dispersed under conditions that inhibit tyrosine phosphatase action, whereas the distribution of the cis-Golgi marker GM130 is insensitive to genistein or pervanadate. By using a specifically reactive biotinylation probe, we detected protein tyrosine phosphatases in highly purified rat liver Golgi membranes. These membranes also contain both endogenous tyrosine kinases and their substrates, indicating that enzymes and substrates for reversible tyrosine phosphorylation are normal membrane-resident components of this trafficking compartment. In the absence of perturbation of actin filaments and microtubules, we conclude that reversible protein tyrosine phosphorylation in the trans-Golgi network is essential for albumin secretion and propose that the constitutive secretion of albumin is in fact a regulated process.

Delayed neuronal death in ischemic hippocampus involves stimulation of protein tyrosine phosphorylation

1996 ◽  
Vol 271 (4) ◽  
pp. C1085-C1097 ◽  
Author(s):  
T. Ohtsuki ◽  
M. Matsumoto ◽  
K. Kitagawa ◽  
T. Mabuchi ◽  
K. Mandai ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Kainic Acid ◽  
Neuronal Death ◽  
Tyrosine Kinases ◽  
Ischemia Reperfusion ◽  
Delayed Neuronal Death ◽  
Mongolian Gerbils ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Stimulation Of

Glutamate triggers neuronal degeneration after ischemia-reperfusion in the brain. However, the details of intracellular signal transduction that propagates cell death remain unknown. The present work investigated whether protein tyrosine phosphorylation mediates neuronal death in the ischemic brain. Transient forebrain ischemia for 5-10 min in Mongolian gerbils or intoxication with the glutamate analogue kainic acid (12 mg/kg) in Sprague-Dawley rats caused neuronal death selectively in the hippocampus 2-4 days or 1 day later, respectively. Under these conditions, 160-, 115-, 105-, 92-, and 85-kDa proteins showed a significant increase in tyrosyl residue phosphorylation selectively in the hippocampus 3-12 h after ischemia or 4-8 h after kainic acid-induced seizures. Tyrosine kinases, including pp60c-src, were activated without a change of tyrosine phosphatases. Administration of radicicol, a selective inhibitor of tyrosine kinases, attenuated stimulation of tyrosine phosphorylation and hippocampal degeneration after ischemia or kainic acid injection. The results suggest that protein tyrosine phosphorylation might propagate delayed neuronal death in the mature hippocampus through glutamate overload after ischemia-reperfusion.

scholarly journals Src Homology 2 Protein Tyrosine Phosphatase (SHPTP2)/Src Homology 2 Phosphatase 2 (SHP2) Tyrosine Phosphatase Is a Positive Regulator of the Interleukin 5 Receptor Signal Transduction Pathways Leading to the Prolongation of Eosinophil Survival

1997 ◽  
Vol 186 (4) ◽  
pp. 561-568 ◽  
Author(s):  
Konrad Pazdrak ◽  
Tetsuya Adachi ◽  
Rafeul Alam
Keyword(s):  
Signal Transduction ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Ras Signaling ◽  
Protein Tyrosine ◽  
Interleukin 5 ◽  
Src Homology 2 ◽  
Eosinophil Survival ◽  
Src Homology

Interleukin-5 (IL-5) regulates the growth and function of eosinophils. It induces rapid tyrosine phosphorylation of Lyn and Jak2 tyrosine kinases. The role of tyrosine phosphatases in IL-5 signal transduction has not been investigated. In this study, we provide first evidence that SH2 protein tyrosine phosphatase 2 (SHPTP2) phosphotyrosine phosphatase plays a key role in prevention of eosinophil death by IL-5. We found that IL-5 produced a rapid activation and tyrosine phosphorylation of SHPTP2 within 1 min. The tyrosine phosphorylated SHPTP2 was complexed with the adapter protein Grb2 in IL-5–stimulated eosinophils. Furthermore, SHPTP2 appeared to physically associate with β common (βc) chain of the IL-5 receptor (IL-5βcR). The association of SHPTP2 with IL-5βcR was reconstituted using a synthetic phosphotyrosine-containing peptide, βc 605–624, encompassing tyrosine (Y)612. The binding to the phosphotyrosine-containing peptide increased the phosphatase activity of SHPTP2, whereas the same peptide with the phosphorylated Y612→ F mutation did not activate SHPTP2. Only SHPTP2 antisense oligonucleotides, but not sense SHPTP2, could inhibit tyrosine phosphorylation of microtubule-associated protein kinase, and reverse the eosinophil survival advantage provided by IL-5. Therefore, we conclude that the physical association of SHPTP2 with the phosphorylated βc receptor and Grb2 and its early activation are required for the coupling of the receptor to the Ras signaling pathway and for prevention of eosinophil death by IL-5.

scholarly journals The Vav Binding Site (Y315) in ZAP-70 Is Critical for Antigen Receptor–mediated Signal Transduction

1997 ◽  
Vol 185 (10) ◽  
pp. 1877-1882 ◽  
Author(s):  
Jun Wu ◽  
Qihong Zhao ◽  
Tomohiro Kurosaki ◽  
Arthur Weiss
Keyword(s):  
Signal Transduction ◽  
B Cell ◽  
Binding Site ◽  
Tyrosine Kinases ◽  
Critical Role ◽  
Antigen Receptor ◽  
Sh2 Domain ◽  
Antigen Receptors ◽  
Antigen Receptor Signaling ◽  
Receptor Ligation

Stimulation of antigen receptors in T and B cells leads to the activation of the Src and Syk families of protein tyrosine kinases (PTK). These PTKs subsequently phosphorylate numerous intracellular substrates, including the 95-kD protooncogene product Vav. Vav is essential for both T and B cell development and T and B cell antigen receptor–mediated signal transduction. After receptor ligation, Vav associates with phosphorylated Syk and ZAP-70 PTKs, an interaction that depends upon its SH2 domain. Here we demonstrate that a point mutation of tyrosine 315 (Y315F) in ZAP-70, a putative Vav SH2 domain binding site, eliminated the Vav– ZAP-70 interaction. Moreover, the Y315 mutation impaired the function of ZAP-70 in antigen receptor signaling. Surprisingly, this mutation also resulted in marked reduction in the tyrosine phosphorylation of ZAP-70, Vav, SLP-76, and Shc. These data demonstrate that the Vav binding site in ZAP-70 plays a critical role in antigen receptor–mediated signal transduction.

scholarly journals Genetic Encoding of A Nonhydrolyzable Phosphotyrosine Analog in Mammalian Cells

2021 ◽  
Author(s):  
Wei Niu ◽  
Jiantao Guo ◽  
Xinyuan He ◽  
Bin Ma ◽  
Yan Chen
Keyword(s):  
Tyrosine Phosphorylation ◽  
Mammalian Cells ◽  
Critical Role ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Practical Applications ◽  
Cellular Processes ◽  
Cellular Events ◽  
Biological Studies ◽  
Model Protein

Protein tyrosine phosphorylation plays a critical role in signal transduction and the regulation of many cellular processes. It is of great significance to understand the underlying regulatory mechanism of particular tyrosine phosphorylation events. Here we report the genetic incorporation of a phosphotyrosine (pTyr) analog, p-carboxymethyl-L-phenylalanine (CMF), into proteins in mammalian cells. This nonhydrolyzable pTyr analog can facilitate biological studies by removing complications caused by the dynamic interconversion between the phosphorylated and non-phosphorylated isoforms of a protein. The developed methodology was demonstrated by using the human signal transducer and activator of transcription-1 (STAT1) as a model protein for homogeneous and defined incorporation of CMF. This tool will greatly enhance our capability to study protein tyrosine phosphorylation-associated biomolecular and cellular events, and enhance biomedical research that target protein tyrosine phosphorylation, which will have a broad impact to both fundamental studies and practical applications.

scholarly journals Identification of a Subset of Common Variable Immunodeficiency Patients with Impaired B-Cell Protein Tyrosine Phosphorylation

1999 ◽  
Vol 6 (6) ◽  
pp. 856-860 ◽  
Author(s):  
Rivka Schwartz ◽  
Yael Ben-Anat Porat ◽  
Zeev Handzel ◽  
Zeev Sthoeger ◽  
Ben-Zion Garty ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
B Cells ◽  
B Cell ◽  
Tyrosine Phosphorylation ◽  
Common Variable Immunodeficiency ◽  
Cell Protein ◽  
Normal Donor ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Common Variable

ABSTRACT The mechanisms responsible for common variable immunodeficiency syndrome (CVID) are as yet unknown. In the present study, we show that the B-cell dysfunction in a subset of CVID patients is caused by defective protein tyrosine phosphorylation (PTP). We demonstrated that the PTP level and immunoglobulin (Ig) secretion malfunctions can be successfully repaired when normal plasma membrane components are implanted into these patients’ B cells. Stimulation of CVID patients’ peripheral blood mononucleated cells with anti-Ig antibody revealed that 7 of 11 patients had lower PTP levels than those found in the normal donor cells. Plasma membrane implantation to the cells of these patients resulted in elevated PTP levels which reached normal levels upon stimulation with anti-human Ig antibody. The results revealed two distinct groups of CVID patients. The first group included patients whose B cells expressed low PTP levels after Ig stimulation. In these patients the plasma membrane implantation restored the normal PTP level as well as the ability to secrete IgM and/or IgG after B-cell stimulation. In the second group, patients whose B cells expressed a normal PTP level after Ig stimulation, with no restoration of their ability to secrete Ig upon plasma membrane implantation and lipopolysaccharide stimulation. We conclude that the first group has an early signal transduction defect located in the B-cell plasma membrane, while in the second group the defect is located elsewhere.

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