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International Journal of Molecular Sciences

International Journal of Molecular Sciences

IF: 5.6
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Pleiotrophin Activates cMet- and mTORC1-Dependent Protein Synthesis through PTPRZ1—The Role of ανβ3 Integrin

Published:9 October 2024 DOI: 10.3390/ijms251910839 PMID: 39409168
Eleni Mourkogianni,?Katerina Karavasili,?Athanasios Xanthopoulos,?Michaela-Karina Enake,?Lydia Menounou,?Evangelia Papadimitriou

Abstract

Pleiotrophin (PTN) is a secreted factor that regulates endothelial cell migration through protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) and αvβ3 integrin. Genetic deletion of Ptprz1 results in enhanced endothelial cell proliferation and migration, due to the decreased expression of β3 integrin and the subsequent, enhanced cMet phosphorylation. In the present study, we investigated the effect of PTN and PTPRZ1 on activating the mTORC1 kinase and protein synthesis and identified part of the implicated signaling pathway in endothelial cells. PTN or genetic deletion of Ptprz1 activates protein synthesis in a mTORC1-dependent manner, as shown by the enhanced phosphorylation of the mTORC1-downstream targets ribosomal protein S6 kinase 1 (SK61) and 4E-binding protein 1 (4EBP1) and the upregulation of HIF-1α. The cMet tyrosine kinase inhibitor crizotinib abolishes the stimulatory effects of PTN or PTPRZ1 deletion on mTORC1 activation and protein synthesis, suggesting that mTORC1 activation is downstream of cMet. The mTORC1 inhibitor rapamycin abolishes the stimulatory effect of PTN or PTPRZ1 deletion on endothelial cell migration, suggesting that mTORC1 is involved in the PTN/PTPRZ1-dependent cell migration. The αvβ3 integrin blocking antibody LM609 and the peptide PTN112-136, both known to bind to ανβ3 and inhibit PTN-induced endothelial cell migration, increase cMet phosphorylation and activate mTORC1, suggesting that cMet and mTORC1 activation are required but are not sufficient to stimulate cell migration. Overall, our data highlight novel aspects of the signaling pathway downstream of the PTN/PTPRZ1 axis that regulates endothelial cell functions.

Substances (6)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Crizotinib 877399-52-5 C21H22Cl2FN5O 618 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O 618 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O 618 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O 618 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O - Inquiry
Crizotinib 877399-52-5 C21H22Cl2FN5O - Inquiry

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