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P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin

P(0)-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 motil...

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Autores principales: Roubelakis, Maria G., Tsaknakis, Grigorios, Lyu, Feng-Juan, Trohatou, Ourania, Zannettino, Andrew C. W., Watt, Suzanne M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290418/
https://www.ncbi.nlm.nih.gov/pubmed/32365526
http://dx.doi.org/10.3390/cells9051100
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author Roubelakis, Maria G.
Tsaknakis, Grigorios
Lyu, Feng-Juan
Trohatou, Ourania
Zannettino, Andrew C. W.
Watt, Suzanne M.
author_facet Roubelakis, Maria G.
Tsaknakis, Grigorios
Lyu, Feng-Juan
Trohatou, Ourania
Zannettino, Andrew C. W.
Watt, Suzanne M.
author_sort Roubelakis, Maria G.
collection PubMed
description P(0)-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.
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spelling pubmed-72904182020-06-15 P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin Roubelakis, Maria G. Tsaknakis, Grigorios Lyu, Feng-Juan Trohatou, Ourania Zannettino, Andrew C. W. Watt, Suzanne M. Cells Article P(0)-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. MDPI 2020-04-29 /pmc/articles/PMC7290418/ /pubmed/32365526 http://dx.doi.org/10.3390/cells9051100 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Roubelakis, Maria G.
Tsaknakis, Grigorios
Lyu, Feng-Juan
Trohatou, Ourania
Zannettino, Andrew C. W.
Watt, Suzanne M.
P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin
title P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin
title_full P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin
title_fullStr P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin
title_full_unstemmed P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin
title_short P(0)-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin
title_sort p(0)-related protein accelerates human mesenchymal stromal cell migration by modulating vla-5 interactions with fibronectin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290418/
https://www.ncbi.nlm.nih.gov/pubmed/32365526
http://dx.doi.org/10.3390/cells9051100
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