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      Protein Tyrosine Kinase Inhibitors Block the Stimulatory Actions of Phosphotyrosine Phosphatase Inhibitors to Increase Cell Proliferation, Alkaline Phosphatase Activity, and Collagen Synthesis in Normal HumanBone Cells

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          Abstract

          The present study sought to test whether inhibition of phosphotyrosine phosphatases (PTPs) would stimulate proliferation and differentiation of normal bone cells, and whether the PTP inhibitor-mediated effects would be blocked by protein tyrosine kinase (PTK) inhibitors. Three inhibitors [phenylarsine oxide (PAO), orthovanadate (VO<sub>4</sub>), and molybdate (MoO<sub>4</sub>)] and two normal human bone cells with different basal differentiation status (i.e., mandible- and vertebra-derived bone cells) were used. Cell proliferation was determined with [<sup>3</sup>H]thymidine incorporation, and confirmed by cell counting. Bone cell differentiation was assessed by increases in alkaline phosphatase (ALP) specific activity and collagen synthesis. The three test PTP inhibitors each stimulated [<sup>3</sup>H]thymidine incorporation in both human bone cell types in a biphasic, dose-dependent manner with optimal doses of 20 n M PAO, 1 μ M VO<sub>4</sub> and 2 μ M MoO<sub>4</sub>, respectively. These PTP inhibitors at mitogenic doses each significantly and reproducibly increased ALP specific activity and collagen synthesis. To determine whether the stimulatory effects of PTP inhibitors could be blocked by PTK inhibitors, the effects of tyrphostin A51 and erbstatin, two potent PTK inhibitors, on the actions of PTK inhibitors on [<sup>3</sup>H]thymidine incorporation and ALP specific activity were evaluated. Both tyrphostin A51 and erbstatin, which by themselves alone significantly inhibited human bone cell proliferation and increased ALP specific activity, completely abolished the stimulatory effects of each of the three test PTP inhibitors on bone cell proliferation and ALP specific activity. In conclusion, these findings confirm the premise that inhibition of PTP activities in normal human bone cells could lead to increases in cell proliferation and differentiation, effects that are independent of basal differentiation status of the cells. More importantly, this study demonstrates for the first time that the stimulatory actions of the PTP inhibitor on bone cell proliferation and ALP could be blocked by a PTK inhibitor, suggesting that the osteogenic effects of PTP inhibitors may depend on PTK activities, presumably to increase basal tyrosyl phosphorylation level. Accordingly, one should interpret results of studies using PTK inhibitors with caution in that an inhibition by a PTK inhibitor does not necessarily indicate the requirement of PTK activities, as it could also suggest involvement of an inhibition of PTPs.

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          Most cited references 6

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          Participation of JAK and STAT proteins in growth hormone-induced signaling.

          The binding of growth hormone leads to dimerization of its receptor, accompanied by phosphorylation and activation of intracellular tyrosine kinases (JAKs) and the latent cytoplasmic transcriptions factors STAT1, STAT3, and STAT5. Both JAK1 and JAK2 are phosphorylated in response to growth hormone in mouse 3T3 F442A and human HT1080 cells. The roles of JAKs in growth hormone signal transduction were examined by using mutant HT1080 cells missing either JAK1 or JAK2. JAK2 is absolutely required for growth hormone-dependent phosphorylation of the receptor, STAT1 and STAT3, JAK1, and the SH2-containing adaptor molecule Shc. In contrast, JAK1 is not required for any of the above functions. These data indicate that JAK2 is both necessary and sufficient for the growth hormone-dependent phosphorylation events required to couple the receptor both to STAT-dependent signaling pathways and to pathways involving Shc. Furthermore, STAT5 is activated by growth hormone in 3T3 F442A cells, but not in HT1080 cells, revealing that the set of STATs activated by growth hormone can vary, possibly contributing to the specificity of the growth hormone response in different cell types.
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            Triggering signaling cascades by receptor tyrosine kinases.

            Growth factor receptors that are tyrosine kinases (RTKs) regulate growth and differentiation of cells in many organisms, including flies, worms, frogs, mice and humans. There has been recent progress in understanding the mechanism by which these receptors transduce signals. Worm and insect studies on RTKs have relied primarily on genetics, while the mammalian studies have employed a combination of molecular genetics and biochemistry. While many RTKs seem to have unique features, there are also many general signal transduction principles that emerge from these studies. In this review, we will focus on common signaling molecules, using RTKs from both vertebrates and invertebrates as examples.
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              Roles of Protein-tyrosine Phosphatases in Stat1 -mediated Cell Signaling

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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2000
                April 2000
                19 April 2000
                : 20
                : 2
                : 153-162
                Affiliations
                Departments of Medicine and Biochemistry, Loma Linda University, and Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial VA Medical Center, Loma Linda, Calif., USA
                Article
                13574 Am J Nephrol 2000;20:153–162
                10.1159/000013574
                10773618
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, Tables: 1, References: 43, Pages: 10
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/13574
                Categories
                Laboratory Investigation

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