Determination of the CD148-Interacting Region in Thrombospondin-1.
CD148 is a transmembrane protein tyrosine phosphatase that is expressed in multiple cell types, including vascular endothelial cells and duct epithelial cells. Previous studies have shown a prominent role of CD148 to reduce growth factor signals and suppress cell proliferation and transformation. Fu...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4858292?pdf=render |
| _version_ | 1818306647361060864 |
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| author | Keiko Takahashi Katherine Sumarriva Rachel Kim Rosie Jiang Dana M Brantley-Sieders Jin Chen Raymond L Mernaugh Takamune Takahashi |
| author_facet | Keiko Takahashi Katherine Sumarriva Rachel Kim Rosie Jiang Dana M Brantley-Sieders Jin Chen Raymond L Mernaugh Takamune Takahashi |
| author_sort | Keiko Takahashi |
| collection | DOAJ |
| description | CD148 is a transmembrane protein tyrosine phosphatase that is expressed in multiple cell types, including vascular endothelial cells and duct epithelial cells. Previous studies have shown a prominent role of CD148 to reduce growth factor signals and suppress cell proliferation and transformation. Further, we have recently shown that thrombospondin-1 (TSP1) serves as a functionally important ligand for CD148. TSP1 has multiple structural elements and interacts with various cell surface receptors that exhibit differing effects. In order to create the CD148-specific TSP1 fragment, here we investigated the CD148-interacting region in TSP1 using a series of TSP1 fragments and biochemical and biological assays. Our results demonstrate that: 1) CD148 binds to the 1st type 1 repeat in TSP1; 2) Trimeric TSP1 fragments that contain the 1st type repeat inhibit cell proliferation in A431D cells that stably express wild-type CD148 (A431D/CD148wt cells), while they show no effects in A431D cells that lack CD148 or express a catalytically inactive form of CD148. The anti-proliferative effect of the TSP1 fragment in A431D/CD148wt cells was largely abolished by CD148 knockdown and antagonized by the 1st, but not the 2nd and 3rd, type 1 repeat fragment. Furthermore, the trimeric TSP1 fragments containing the 1st type repeat increased the catalytic activity of CD148 and reduced phospho-tyrosine contents of EGFR and ERK1/2, defined CD148 substrates. These effects were not observed in the TSP1 fragments that lack the 1st type 1 repeat. Last, we demonstrate that the trimeric TSP1 fragment containing the 1st type 1 repeat inhibits endothelial cell proliferation in culture and angiogenesis in vivo. These effects were largely abolished by CD148 knockdown or deficiency. Collectively, these findings indicate that the 1st type 1 repeat interacts with CD148, reducing growth factor signals and inhibiting epithelial or endothelial cell proliferation and angiogenesis. |
| first_indexed | 2024-12-13T06:45:48Z |
| format | Article |
| id | doaj.art-4c3d21522e9648468c2f1f37a5d9df9e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T06:45:48Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-4c3d21522e9648468c2f1f37a5d9df9e2022-12-21T23:56:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01115e015491610.1371/journal.pone.0154916Determination of the CD148-Interacting Region in Thrombospondin-1.Keiko TakahashiKatherine SumarrivaRachel KimRosie JiangDana M Brantley-SiedersJin ChenRaymond L MernaughTakamune TakahashiCD148 is a transmembrane protein tyrosine phosphatase that is expressed in multiple cell types, including vascular endothelial cells and duct epithelial cells. Previous studies have shown a prominent role of CD148 to reduce growth factor signals and suppress cell proliferation and transformation. Further, we have recently shown that thrombospondin-1 (TSP1) serves as a functionally important ligand for CD148. TSP1 has multiple structural elements and interacts with various cell surface receptors that exhibit differing effects. In order to create the CD148-specific TSP1 fragment, here we investigated the CD148-interacting region in TSP1 using a series of TSP1 fragments and biochemical and biological assays. Our results demonstrate that: 1) CD148 binds to the 1st type 1 repeat in TSP1; 2) Trimeric TSP1 fragments that contain the 1st type repeat inhibit cell proliferation in A431D cells that stably express wild-type CD148 (A431D/CD148wt cells), while they show no effects in A431D cells that lack CD148 or express a catalytically inactive form of CD148. The anti-proliferative effect of the TSP1 fragment in A431D/CD148wt cells was largely abolished by CD148 knockdown and antagonized by the 1st, but not the 2nd and 3rd, type 1 repeat fragment. Furthermore, the trimeric TSP1 fragments containing the 1st type repeat increased the catalytic activity of CD148 and reduced phospho-tyrosine contents of EGFR and ERK1/2, defined CD148 substrates. These effects were not observed in the TSP1 fragments that lack the 1st type 1 repeat. Last, we demonstrate that the trimeric TSP1 fragment containing the 1st type 1 repeat inhibits endothelial cell proliferation in culture and angiogenesis in vivo. These effects were largely abolished by CD148 knockdown or deficiency. Collectively, these findings indicate that the 1st type 1 repeat interacts with CD148, reducing growth factor signals and inhibiting epithelial or endothelial cell proliferation and angiogenesis.http://europepmc.org/articles/PMC4858292?pdf=render |
| spellingShingle | Keiko Takahashi Katherine Sumarriva Rachel Kim Rosie Jiang Dana M Brantley-Sieders Jin Chen Raymond L Mernaugh Takamune Takahashi Determination of the CD148-Interacting Region in Thrombospondin-1. PLoS ONE |
| title | Determination of the CD148-Interacting Region in Thrombospondin-1. |
| title_full | Determination of the CD148-Interacting Region in Thrombospondin-1. |
| title_fullStr | Determination of the CD148-Interacting Region in Thrombospondin-1. |
| title_full_unstemmed | Determination of the CD148-Interacting Region in Thrombospondin-1. |
| title_short | Determination of the CD148-Interacting Region in Thrombospondin-1. |
| title_sort | determination of the cd148 interacting region in thrombospondin 1 |
| url | http://europepmc.org/articles/PMC4858292?pdf=render |
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