β-caryophyllene oxide inhibits constitutive and inducible STAT3 signaling pathway through induction of the SHP-1 protein tyrosine phosphatase

2013 ◽  
Vol 53 (10) ◽  
pp. 793-806 ◽  
Author(s):  
Chulwon Kim ◽  
Somi K. Cho ◽  
Shweta Kapoor ◽  
Ansu Kumar ◽  
Shireen Vali ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Caryophyllene Oxide ◽  
Protein Tyrosine ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Anaplastic Lymphoma Kinase Is Activated through the Pleiotrophin/Receptor Protein Tyrosine Phosphatase (RPTP)β/ζ Signaling Pathway: A Unique Mechanism of Activation of Receptor Protein Tyrosine Kinases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4355-4355
Author(s):  
Pablo Perez-Pinera ◽  
Wei Zhang ◽  
Zhaoyi Wang ◽  
James R. Berenson ◽  
Thomas F. Deuel
Keyword(s):  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Anaplastic Lymphoma ◽  
Unique Mechanism

Abstract Anaplastic Lymphoma Kinase (ALK) is a receptor-type transmembrane tyrosine kinase (RTK) of the insulin receptor superfamily that structurally is most closely related to leukocyte tyrosine kinase. It was first discovered as a chimeric protein (NPM-ALK) of nucleophosmin and the C-terminal (kinase) domain of ALK in anaplastic large cell lymphomas (ALCL). NPM-ALK is constitutively active and generates the oncogenic signals that are the pathogenic mechanisms of these highly malignant cancers. The full-length ALK also is believed to have an important role in the pathogenesis of other human malignancies, since its expression is found in rhabdomyosarcomas, neuroblastomas, neuroectodermal tumors, glioblastomas, breast carcinomas, and melanomas. Recently it was proposed that pleiotrophin (PTN the protein, Ptn the gene) is the ligand that stimulates ALK to transduce signals to activate downstream targets. However, this proposal contrasted with earlier studies that demonstrated Receptor Protein Tyrosine Phosphatase (RPTP)β/ζ is the functional receptor for PTN. PTN was shown to inactivate RPTPβ/ζ and thereby permit the activity of different tyrosine kinases to increase tyrosine phosphorylation of the substrates of RPTPβ/ζ at the sites that are dephosphorylated by RPTPβ/ζ in cells not stimulated by PTN. Subsequent studies identified β-catenin, β-adducin, Fyn, GIT1/Cat-1, P190RhoGAP, and histone deacetylase 2 (HDAC-2) as downstream targets of the PTN/RPTPβ/ζ signaling pathway and demonstrated that their levels of tyrosine phosphorylation increase in PTN-stimulated cells. This diversity of PTN-regulated targets is one basis for the pleiotrophic activities of PTN. We now demonstrate that tyrosine phosphorylation of ALK is increased in PTN-stimulated cells through the PTN/RPTPβ/ζ signaling pathway. It is furthermore shown that ALK is activated in PTN-stimulated cells when it is expressed in cells without its extracellular domain, that β-catenin is a substrate of ALK, that the tyrosine phosphorylation site in β-catenin phosphorylated by ALK is the same site dephosphorylated by RPTPβ/ζ, and that PTN-stimulated tyrosine phosphorylation of β-catenin requires expression of ALK. The data suggest a unique mechanism to activate ALK; the data support a mechanism in which β-catenin is phosphorylated in tyrosine through the coordinated inactivation of RPTPβ/ζ, the activation of the tyrosine kinase activity of ALK, and the phosphorylation of β-catenin by ALK at the same site regulated by RPTPβ/ζ in PTN-stimulated cells. Since PTN often is inappropriately expressed in the same malignancies that express ALK, the data suggest a mechanism through which ALK signaling may contribute to those malignancies that express full length ALK through the activity of PTN to signal constitutively the same pathways as NPM-ALK in ALCL.

scholarly journals Stat6 and IRS-2 Cooperate in Interleukin 4 (IL-4)-Induced Proliferation and Differentiation but Are Dispensable for IL-4-Dependent Rescue from Apoptosis

2002 ◽  
Vol 22 (1) ◽  
pp. 117-126 ◽  
Author(s):  
Andrea L. Wurster ◽  
Dominic J. Withers ◽  
Tohru Uchida ◽  
Morris F. White ◽  
Michael J. Grusby
Keyword(s):  
T Cells ◽  
Signaling Pathway ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Interleukin 4 ◽  
Signaling Proteins ◽  
Protein Tyrosine ◽  
Antiapoptotic Effect ◽  
Induced Changes

ABSTRACT Stat6 and IRS-2 are two important signaling proteins that associate with the cytoplasmic tail of the interleukin 4 (IL-4) receptor. Data from numerous in vitro experiments have led to a model for IL-4 signal transduction in which the Stat6 signaling pathway is responsible for the IL-4 induced changes in gene expression and differentiation events, while the IRS-2 signaling pathway provides mitogenic and antiapoptotic signals. In order to determine the relative contributions of these signaling molecules in primary lymphocytes, we have examined IL-4 responses in T cells from mice deficient for either Stat6 or IRS-2 as well as from mice doubly deficient for both genes. Both IRS-2 and, especially, Stat6 are shown to be critically involved in IL-4-induced proliferation of T cells, presumably through the cooperative regulation of the Cdk inhibitor p27kip1. Like Stat6-deficient Th cells, IRS-2-deficient cells are also compromised in their ability to secrete Th2 cytokines, revealing a previously unrecognized role for IRS-2 in Th2 cell development. Although Stat6 and/or IRS-2 expression is required for IL-4-induced proliferative and differentiative responses, both signaling proteins are dispensable for the antiapoptotic effect of IL-4. However, treatment of lymphocytes with a protein tyrosine phosphatase inhibitor is able to block the antiapoptotic effect of IL-4 specifically in Stat6- or IRS-2-deficient cells and not in wild-type cells. Our results suggest that Stat6 and IRS-2 cooperate in promoting both IL-4-induced proliferative and differentiating responses, while an additional signaling mediator that depends on protein tyrosine phosphatase activity contributes to the antiapoptotic activities of IL-4 in primary T cells.

scholarly journals Cell cycle-dependent regulation of SFK, JAK1 and STAT3 signaling by the protein tyrosine phosphatase TCPTP

Cell Cycle ◽  
2008 ◽  
Vol 7 (21) ◽  
pp. 3405-3416 ◽  
Author(s):  
Ben J. Shields ◽  
Naomi W. Court ◽  
Christine Hauser ◽  
Patricia E. Bukczynska ◽  
Tony Tiganis
Keyword(s):  
Cell Cycle ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Stat3 Signaling ◽  
Cycle Dependent
Sign in / Sign up

Export Citation Format

Share Document