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Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells
The dysregulation of receptor protein tyrosine kinase (RPTK) function can result in changes in cell proliferation, cell growth and metastasis leading to malignant transformation. Among RPTKs, the TAM receptor family composed of three members Tyro3, Axl, and Mer has been recognized to have a prominen...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351477/ https://www.ncbi.nlm.nih.gov/pubmed/22606290 http://dx.doi.org/10.1371/journal.pone.0036800 |
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author | Brown, Jessica E. Krodel, Meredith Pazos, Mauricio Lai, Cary Prieto, Anne L. |
author_facet | Brown, Jessica E. Krodel, Meredith Pazos, Mauricio Lai, Cary Prieto, Anne L. |
author_sort | Brown, Jessica E. |
collection | PubMed |
description | The dysregulation of receptor protein tyrosine kinase (RPTK) function can result in changes in cell proliferation, cell growth and metastasis leading to malignant transformation. Among RPTKs, the TAM receptor family composed of three members Tyro3, Axl, and Mer has been recognized to have a prominent role in cell transformation. In this study we analyzed the consequences of Tyro3 overexpression on cell proliferation, activation of signaling pathways and its functional interactions with Axl. Overexpression of Tyro3 in the Rat2 cell line that expresses Axl, but not Mer or Tyro3, resulted in a 5 fold increase in cell proliferation. This increase was partially blocked by inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway but not by inhibitors of the phosphatidylinositol 3-kinase (PI(3)K) signaling pathway. Consistent with these findings, an increase in ERK1/2 phosphorylation was detected with Tyro3 but not with Axl overexpression. In contrast, activation of Axl stimulated the PI(3)K pathway, which was mitigated by co-expression of Tyro3. The overexpression of Tyro3 enhanced Gas6-mediated Axl phosphorylation, which was not detected upon overexpression of a “kinase dead” form of Tyro3 (kdTyro3). In addition, the overexpression of Axl induced kdTyro3 phosphorylation. Co-immunoprecipitation experiments confirmed that the Axl and Tyro3 receptors are closely associated. These findings show that overexpression of Tyro3 in the presence of Axl promotes cell proliferation, and that co-expression of Axl and Tyro3 can affect the outcome of Gas6-initiated signaling. Furthermore, they demonstrate a functional interaction between the members of the TAM receptor family which can shed light on the molecular mechanisms underlying the functional consequences of TAM receptor activation in cell transformation, neural function, immune function, and reproductive function among others. |
format | Online Article Text |
id | pubmed-3351477 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33514772012-05-17 Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells Brown, Jessica E. Krodel, Meredith Pazos, Mauricio Lai, Cary Prieto, Anne L. PLoS One Research Article The dysregulation of receptor protein tyrosine kinase (RPTK) function can result in changes in cell proliferation, cell growth and metastasis leading to malignant transformation. Among RPTKs, the TAM receptor family composed of three members Tyro3, Axl, and Mer has been recognized to have a prominent role in cell transformation. In this study we analyzed the consequences of Tyro3 overexpression on cell proliferation, activation of signaling pathways and its functional interactions with Axl. Overexpression of Tyro3 in the Rat2 cell line that expresses Axl, but not Mer or Tyro3, resulted in a 5 fold increase in cell proliferation. This increase was partially blocked by inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway but not by inhibitors of the phosphatidylinositol 3-kinase (PI(3)K) signaling pathway. Consistent with these findings, an increase in ERK1/2 phosphorylation was detected with Tyro3 but not with Axl overexpression. In contrast, activation of Axl stimulated the PI(3)K pathway, which was mitigated by co-expression of Tyro3. The overexpression of Tyro3 enhanced Gas6-mediated Axl phosphorylation, which was not detected upon overexpression of a “kinase dead” form of Tyro3 (kdTyro3). In addition, the overexpression of Axl induced kdTyro3 phosphorylation. Co-immunoprecipitation experiments confirmed that the Axl and Tyro3 receptors are closely associated. These findings show that overexpression of Tyro3 in the presence of Axl promotes cell proliferation, and that co-expression of Axl and Tyro3 can affect the outcome of Gas6-initiated signaling. Furthermore, they demonstrate a functional interaction between the members of the TAM receptor family which can shed light on the molecular mechanisms underlying the functional consequences of TAM receptor activation in cell transformation, neural function, immune function, and reproductive function among others. Public Library of Science 2012-05-14 /pmc/articles/PMC3351477/ /pubmed/22606290 http://dx.doi.org/10.1371/journal.pone.0036800 Text en Brown et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Brown, Jessica E. Krodel, Meredith Pazos, Mauricio Lai, Cary Prieto, Anne L. Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells |
title | Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells |
title_full | Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells |
title_fullStr | Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells |
title_full_unstemmed | Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells |
title_short | Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells |
title_sort | cross-phosphorylation, signaling and proliferative functions of the tyro3 and axl receptors in rat2 cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351477/ https://www.ncbi.nlm.nih.gov/pubmed/22606290 http://dx.doi.org/10.1371/journal.pone.0036800 |
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