P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin
P<sub>0</sub>-related protein (PZR), a Noonan and LEOPARD syndrome target, is a member of the transmembrane Immunoglobulin superfamily. Its cytoplasmic tail contains two immune-receptor tyrosine-based inhibitory motifs (ITIMs), implicated in adhesion-dependent signaling and regulating ce...
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MDPI AG
2020-04-01
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| author | Maria G. Roubelakis Grigorios Tsaknakis Feng-Juan Lyu Ourania Trohatou Andrew C. W. Zannettino Suzanne M. Watt |
| author_facet | Maria G. Roubelakis Grigorios Tsaknakis Feng-Juan Lyu Ourania Trohatou Andrew C. W. Zannettino Suzanne M. Watt |
| author_sort | Maria G. Roubelakis |
| collection | DOAJ |
| description | P<sub>0</sub>-related protein (PZR), a Noonan and LEOPARD syndrome target, is a member of the transmembrane Immunoglobulin superfamily. Its cytoplasmic tail contains two immune-receptor tyrosine-based inhibitory motifs (ITIMs), implicated in adhesion-dependent signaling and regulating cell adhesion and motility. PZR promotes cell migration on the extracellular matrix (ECM) molecule, fibronectin, by interacting with SHP-2 (Src homology-2 domain-containing protein tyrosine phosphatase-2), a molecule essential for skeletal development and often mutated in Noonan and LEOPARD syndrome patients sharing overlapping musculoskeletal abnormalities and cardiac defects. To further explore the role of PZR, we assessed the expression of PZR and its ITIM-less isoform, PZRb, in human bone marrow mesenchymal stromal cells (hBM MSC), and its ability to facilitate adhesion to and spreading and migration on various ECM molecules. Furthermore, using siRNA knockdown, confocal microscopy, and immunoprecipitation assays, we assessed PZR and PZRb interactions with β1 integrins. PZR was the predominant isoform in hBM MSC. Migrating hBM MSCs interacted most effectively with fibronectin and required the association of PZR, but not PZRb, with the integrin, VLA-5(α5β1), leading to modulation of focal adhesion kinase phosphorylation and vinculin levels. This raises the possibility that dysregulation of PZR function may modify hBM MSC migratory behavior, potentially contributing to skeletal abnormalities. |
| first_indexed | 2024-03-10T20:09:25Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:09:25Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-560258349fb64a068e53dad241c920f92023-11-19T23:00:50ZengMDPI AGCells2073-44092020-04-0195110010.3390/cells9051100P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with FibronectinMaria G. Roubelakis0Grigorios Tsaknakis1Feng-Juan Lyu2Ourania Trohatou3Andrew C. W. Zannettino4Suzanne M. Watt5Laboratory of Biology, National and Kapodistrian University of Athens Medical School, 115 27 Athens, GreeceStem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9BQ, UKStem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9BQ, UKLaboratory of Biology, National and Kapodistrian University of Athens Medical School, 115 27 Athens, GreeceAdelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide 5005, AustraliaStem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9BQ, UKP<sub>0</sub>-related protein (PZR), a Noonan and LEOPARD syndrome target, is a member of the transmembrane Immunoglobulin superfamily. Its cytoplasmic tail contains two immune-receptor tyrosine-based inhibitory motifs (ITIMs), implicated in adhesion-dependent signaling and regulating cell adhesion and motility. PZR promotes cell migration on the extracellular matrix (ECM) molecule, fibronectin, by interacting with SHP-2 (Src homology-2 domain-containing protein tyrosine phosphatase-2), a molecule essential for skeletal development and often mutated in Noonan and LEOPARD syndrome patients sharing overlapping musculoskeletal abnormalities and cardiac defects. To further explore the role of PZR, we assessed the expression of PZR and its ITIM-less isoform, PZRb, in human bone marrow mesenchymal stromal cells (hBM MSC), and its ability to facilitate adhesion to and spreading and migration on various ECM molecules. Furthermore, using siRNA knockdown, confocal microscopy, and immunoprecipitation assays, we assessed PZR and PZRb interactions with β1 integrins. PZR was the predominant isoform in hBM MSC. Migrating hBM MSCs interacted most effectively with fibronectin and required the association of PZR, but not PZRb, with the integrin, VLA-5(α5β1), leading to modulation of focal adhesion kinase phosphorylation and vinculin levels. This raises the possibility that dysregulation of PZR function may modify hBM MSC migratory behavior, potentially contributing to skeletal abnormalities.https://www.mdpi.com/2073-4409/9/5/1100human bone marrow stromal cellsPZRSHP-2cell adhesion moleculesfibroblastsITIM |
| spellingShingle | Maria G. Roubelakis Grigorios Tsaknakis Feng-Juan Lyu Ourania Trohatou Andrew C. W. Zannettino Suzanne M. Watt P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin Cells human bone marrow stromal cells PZR SHP-2 cell adhesion molecules fibroblasts ITIM |
| title | P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin |
| title_full | P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin |
| title_fullStr | P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin |
| title_full_unstemmed | P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin |
| title_short | P<sub>0</sub>-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin |
| title_sort | p sub 0 sub related protein accelerates human mesenchymal stromal cell migration by modulating vla 5 interactions with fibronectin |
| topic | human bone marrow stromal cells PZR SHP-2 cell adhesion molecules fibroblasts ITIM |
| url | https://www.mdpi.com/2073-4409/9/5/1100 |
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