The urokinase receptor (uPAR) stimulates cell proliferation by forming a macromolecular complex with αvβ3 integrin and the epidermal growth factor receptor (EGFR, ErbB1 or HER1) that we name the uPAR proliferasome. uPAR transactivates EGFR, which in turn mediates uPAR-initiated mitogenic signal to the cell. EGFR activation and EGFR-dependent cell growth are blocked in the absence of uPAR expression or when uPAR activity is inhibited by antibodies against either uPAR or EGFR. The mitogenic sequence of uPAR corresponds to the D2A motif present in domain 2. NMR analysis revealed that D2A synthetic peptide has a particular three-dimensional structure, which is atypical for short peptides. D2A peptide is as effective as EGF in promoting EGFR phosphorylation and cell proliferation that were inhibited by AG1478, a specific inhibitor of the tyrosine kinase activity of EGFR. Both D2A and EGF failed to induce proliferation of NR6-EGFR-K721A cells expressing a kinase-defective mutant of EGFR. Moreover, D2A peptide and EGF phosphorylate ERK demonstrating the involvement of the MAP kinase signalling pathway. Altogether, this study reveals the importance of sequence D2A of uPAR, and the interdependence of uPAR and EGFR.

D2A sequence of the urokinase receptor induces cell growth through αvβ3 integrin and EGFR / G. Eden, M. Archinti, R. Arnaudova, G. Andreotti, A. Motta, F. Furlan, V. Citro, M.V. Cubellis, B. Degryse. - In: CELLULAR AND MOLECULAR LIFE SCIENCES. - ISSN 1420-682X. - 75:10(2018 May), pp. 1889-1907. [10.1007/s00018-017-2718-3]

D2A sequence of the urokinase receptor induces cell growth through αvβ3 integrin and EGFR

V. Citro;
2018-05

Abstract

The urokinase receptor (uPAR) stimulates cell proliferation by forming a macromolecular complex with αvβ3 integrin and the epidermal growth factor receptor (EGFR, ErbB1 or HER1) that we name the uPAR proliferasome. uPAR transactivates EGFR, which in turn mediates uPAR-initiated mitogenic signal to the cell. EGFR activation and EGFR-dependent cell growth are blocked in the absence of uPAR expression or when uPAR activity is inhibited by antibodies against either uPAR or EGFR. The mitogenic sequence of uPAR corresponds to the D2A motif present in domain 2. NMR analysis revealed that D2A synthetic peptide has a particular three-dimensional structure, which is atypical for short peptides. D2A peptide is as effective as EGF in promoting EGFR phosphorylation and cell proliferation that were inhibited by AG1478, a specific inhibitor of the tyrosine kinase activity of EGFR. Both D2A and EGF failed to induce proliferation of NR6-EGFR-K721A cells expressing a kinase-defective mutant of EGFR. Moreover, D2A peptide and EGF phosphorylate ERK demonstrating the involvement of the MAP kinase signalling pathway. Altogether, this study reveals the importance of sequence D2A of uPAR, and the interdependence of uPAR and EGFR.
Cell proliferation; EGF receptor; Integrin; Macromolecular complex; Signal transduction; Urokinase receptor; Amino Acid Sequence; Cell Line, Tumor; ErbB Receptors; HEK293 Cells; Humans; Integrin alphaVbeta3; MAP Kinase Signaling System; Models, Molecular; Phosphorylation; Receptors, Urokinase Plasminogen Activator; Cell Proliferation
Settore BIO/10 - Biochimica
Settore MED/04 - Patologia Generale
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/724684
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