Physiological Signaling Specificity by Protein Tyrosine Phosphatases

Physiology ◽  
2009 ◽  
Vol 24 (5) ◽  
pp. 281-289 ◽  
Author(s):  
Matthew Soulsby ◽  
Anton M. Bennett
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Physiological Responses ◽  
Cell Movement ◽  
Protein Tyrosine Phosphatases ◽  
Biological Processes ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Signaling Specificity

Protein tyrosine phosphatases (PTPs) are now recognized to be involved in a multitude of signaling events that control fundamental biological processes such as cell growth, differentiation, apoptosis, and cell movement. PTPs, which were initially thought to be less discriminating in their actions compared with their protein tyrosine kinase counterparts, are now known to regulate these various biological processes in a precise manner. This review will focus on the concept that PTPs exhibit remarkable signaling specificity through intrinsic differences between their PTP domains and through various modes of regulation that endows them with the capacity to promote unique physiological responses.

scholarly journals Mice Devoid of Fer Protein-Tyrosine Kinase Activity Are Viable and Fertile but Display Reduced Cortactin Phosphorylation

2001 ◽  
Vol 21 (2) ◽  
pp. 603-613 ◽  
Author(s):  
Andrew W. B. Craig ◽  
Ralph Zirngibl ◽  
Karen Williams ◽  
Lesley-Ann Cole ◽  
Peter A. Greer
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Cell Growth ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Focal Adhesions ◽  
Embryonic Fibroblasts ◽  
Protein Tyrosine ◽  
Phenotypic Differences

ABSTRACT The ubiquitous Fer protein-tyrosine kinase has been proposed to regulate diverse processes such as cell growth, cell adhesion, and neurite outgrowth. To gain insight into the biological function of Fer, we have targeted the fer locus with a kinase-inactivating missense mutation (ferD743R ). Mice homozygous for this mutation develop normally, have no overt phenotypic differences from wild-type mice, and are fertile. Since these mice lack both Fer and the testis-specific FerT kinase activities, these proteins are clearly not essential for development and survival. No differences were observed in overall cellularity of bone marrow, spleen, or thymus in the absence of Fer activity. While most platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation was unchanged inferD743R homozygous embryonic fibroblasts, cortactin phosphorylation was reduced. However, Fer kinase activity was not required for PDGF-induced Stat3, p120ctn, or epidermal growth factor (EGF)-induced β-catenin phosphorylation. Also, no defects were observed in changes to the actin cytoskeleton, adherens junctions, or focal adhesions in PDGF- or EGF-stimulatedferD743R homozygous embryonic fibroblasts. Therefore, Fer likely serves a redundant role in regulating cell growth, cell adhesion, retinal development, and spermatogenesis but is required for efficient phosphorylation of cortactin.

Inhibition by 5′-methylthioadenosine of cell growth and tyrosine kinase activity stimulated by fibroblast growth factor receptor in human gliomas

1995 ◽  
Vol 83 (4) ◽  
pp. 690-697 ◽  
Author(s):  
Katsuya Miyaji ◽  
Eiichi Tani ◽  
Atsuhisa Nakano ◽  
Hideyasu Ikemoto ◽  
Keizo Kaba
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Glioma Cells ◽  
Protein Tyrosine Phosphorylation ◽  
Tyrosine Kinase Activity ◽  
Protein Tyrosine

✓ Stimulation of three human glioma cell lines with basic fibroblast growth factor (bFGF) led to the enhancement of cell growth and the rapid tyrosine phosphorylation of cellular proteins, including major substrates of 90 kD. A methyltransferase inhibitor, 5′-methylthioadenosine (MTA), inhibited dose dependently the bFGF-stimulated cell growth and protein tyrosine phosphorylation in glioma cells by blocking both receptor autophosphorylation and substrate phosphorylation, as shown by immunoblotting with antiphosphotyrosine antibodies and cross-linking bFGF to receptors. The antiproliferative activity of MTA correlated quantitatively with its potency as an inhibitor of bFGF-stimulated protein tyrosine kinase activity. The methyltransferase inhibitor MTA had no effect on either epidermal growth factor— or platelet-derived growth factor—stimulated protein tyrosine phosphorylation in glioma cells, but inhibited specifically bFGF-stimulated protein tyrosine kinase activity. The concentration of MTA required for inhibition of protein methylation correlated well with the concentration required for inhibition of bFGF-stimulated cell growth and protein tyrosine phosphorylation. Because MTA had no effect on numbers and dissociation constants of high- and low-affinity bFGF receptors, the inhibition of bFGF-stimulated bFGF receptor tyrosine kinase activity is not likely to be the result of a reduction in bFGF receptor and bFGF binding capacity. In fact, MTA delayed and reduced the internalization and nuclear translocation of bFGF, and the internalized bFGF was submitted to a limited proteolysis that converted it to lower molecular peptides whose presence remained for at least 22 hours. The effect of MTA on bFGF-stimulated tyrosine phosphorylation was immediate and readily reversible.

scholarly journals SH2 Domain-Mediated Interaction of Inhibitory Protein Tyrosine Kinase Csk with Protein Tyrosine Phosphatase-HSCF

2001 ◽  
Vol 21 (4) ◽  
pp. 1077-1088 ◽  
Author(s):  
Bing Wang ◽  
Serge Lemay ◽  
Schickwann Tsai ◽  
André Veillette
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Protein Tyrosine Phosphatases ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Negative Regulator ◽  
Yeast Cells ◽  
Inhibitory Protein ◽  
Protein Tyrosine

ABSTRACT The protein tyrosine kinase (PTK) Csk is a potent negative regulator of several signal transduction processes, as a consequence of its exquisite ability to inactivate Src-related PTKs. This function requires not only the kinase domain of Csk, but also its Src homology 3 (SH3) and SH2 regions. We showed previously that the Csk SH3 domain mediates highly specific associations with two members of the PEP family of nonreceptor protein tyrosine phosphatases (PTPs), PEP and PTP-PEST. In comparison, the Csk SH2 domain interacts with several tyrosine phosphorylated molecules, presumed to allow targetting of Csk to sites of Src family kinase activation. Herein, we attempted to understand better the regulation of Csk by identifying ligands for its SH2 domain. Using a modified yeast two-hybrid screen, we uncovered the fact that Csk associates with PTP-HSCF, the third member of the PEP family of PTPs. This association was documented not only in yeast cells but also in a heterologous mammalian cell system and in cytokine-dependent hemopoietic cells. Surprisingly, the Csk–PTP-HSCF interaction was found to be mediated by the Csk SH2 domain and two putative sites of tyrosine phosphorylation in the noncatalytic portion of PTP-HSCF. Transfection experiments indicated that Csk and PTP-HSCF synergized to inhibit signal transduction by Src family kinases and that this cooperativity was dependent on the domains mediating their association. Finally, we obtained evidence that PTP-HSCF inactivated Src-related PTKs by selectively dephosphorylating the positive regulatory tyrosine in their kinase domain. Taken together, these results demonstrate that part of the function of the Csk SH2 domain is to mediate an inducible association with a PTP, thereby engineering a more efficient inhibitory mechanism for Src-related PTKs. Coupled with previously published observations, these data also establish that Csk forms complexes with all three known members of the PEP family.

The CD4/CD8:p56lck complex in T lymphocytes: a potential mechanism to regulate T-cell growth

1989 ◽  
Vol 67 (9) ◽  
pp. 581-589 ◽  
Author(s):  
Christopher Rudd ◽  
Stuart Helms ◽  
Elizabeth K. Barber ◽  
Stuart F. Schlossman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Active Form ◽  
Protein Tyrosine ◽  
Catalytically Active ◽  
T Cell Growth

The CD4 and CD8 antigens on the surface of T cells appear to bind to major histocompatibility complex (MHC) class II and I antigens, respectively. These receptors have also been found to regulate T cell growth in a manner independent of MHC recognition. In this report, we describe recent work showing that the CD4 and CD8 receptors are coupled to a protein-tyrosine kinase, p56lck, from T lymphocytes. The p56lck protein is a member of the src family, which plays a crucial role in the activation and transformation of various mammalian cells. The CD4/CD8:p56ck complex is catalytically active as shown by its ability to phosphorylate at 55–60 kDa. Two-dimensional, nonequilibrium gel electrophoresis demonstrated the similarity of p56lck associated with the CD4 and CD8 antigens. Detergents were found to vary in their ability to solubilize the CD4:p56lck complex in a catalytically active form. We further demonstrated by in vitro phosphorylation that members of the CD3 complex including the γ, δ, and ε chains, as well as a putative ζ subunit can be phosphorylated at tyrosyl residues by the CD4/CD8:p56lck complex. Thus, this interaction may play an important role in the activation of T cells, and may mediate the cooperative interaction between the CD4/CD8 antigens and the Ti(TcR)/CD3 complex. This interaction also represents a possible precedent by which other members of the src family (c-src, c-yes, c-fgr, etc.) may be found to interact with mammalian growth receptors.Key words: CD4, CD8, protein-tyrosine kinase p56lck.

scholarly journals Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

2021 ◽  
Vol 9 ◽  
Author(s):  
Caroline E. Nunes-Xavier ◽  
Laura Zaldumbide ◽  
Lorena Mosteiro ◽  
Ricardo López-Almaraz ◽  
Nagore García de Andoin ◽  
...  
Keyword(s):  
Cell Growth ◽  
Intracellular Signaling ◽  
Current Knowledge ◽  
Neuroblastoma Cell ◽  
Protein Tyrosine Phosphatases ◽  
Specific Protein ◽  
Neuroendocrine Cells ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Incidence And Mortality

Neuroblastoma is a type of cancer intimately related with early development and differentiation of neuroendocrine cells, and constitutes one of the pediatric cancers with higher incidence and mortality. Protein tyrosine phosphatases (PTPs) are key regulators of cell growth and differentiation by their direct effect on tyrosine dephosphorylation of specific protein substrates, exerting major functions in the modulation of intracellular signaling during neuron development in response to external cues driving cell proliferation, survival, and differentiation. We review here the current knowledge on the role of PTPs in neuroblastoma cell growth, survival, and differentiation. The potential of PTPs as biomarkers and molecular targets for inhibition in neuroblastoma therapies is discussed.

Protein-tyrosine Kinase p72 syk Is Activated by Platelet Activating Factor in Platelets

1994 ◽  
Vol 72 (06) ◽  
pp. 937-941 ◽  
Author(s):  
Karim Rezaul ◽  
Shigeru Yanagi ◽  
Kiyonao Sada ◽  
Takanobu Taniguchi ◽  
Hirohei Yamamura
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Kinase Assay ◽  
Potential Candidate ◽  
Protein Tyrosine ◽  
Induced Aggregation

SummaryIt has been demonstrated that activation of platelets by platelet-activating factor (PAF) results in a dramatic increase in tyrosine phosphorylation of several cellular proteins. We report here that p72 syk is a potential candidate for the protein-tyrosine phosphorylation following PAF stimulation in porcine platelets. Immunoprecipitation kinase assay revealed that PAF stimulation resulted in a rapid activation of p72 syk which peaked at 10 s. The level of activation was found to be dose dependent and could be completely inhibited by the PAF receptor antagonist, CV3988. Phosphorylation at the tyrosine residues of p72 syk coincided with activation of yllsyk. Pretreatment of platelets with aspirin and apyrase did not affect PAF induced activation of p72 syk .Furthermore, genistein, a potent protein-tyrosine-kinase inhibitor, diminished PAF-induced p72 syk activation and Ca2+ mobilization as well as platelet aggregation. These results suggest that p72 syk may play a critical role in PAF-induced aggregation, possibly through regulation of Ca2+ mobilization.

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