The tyrosine kinase Ron, receptor for MSP (macrophage-stimulating protein), displays several serine residues of unknown functions. Using [32P]H3PO4 metabolic labelling, we found that Ron is serine-phosphorylated and dephosphorylated in vitro by PP1 (protein phosphatase 1). PP1 associates with Ron obtained from cells of different origins. The association is stimulated by MSP or serum and is prevented by wortmannin, an inhibitor of the Akt/PKB (protein serine/threonine kinase B) pathway. Akt/PKB phosphorylates Ron Ser-1394, thus providing a docking site for 14-3-3 (scaffold proteins binding to phosphoserine/phosphothreonine-containing sequences). In living cells, PP1 binds to the Ron mutant S1394A, but the association is no longer regulated by serum, MSP or wortmannin. The role of PP1 association with Ron is highlighted by (1) Ser-1394 dephosphorylation by PP1 in vitro and in living cells, (2) loss of 14-3-3 association with Ron after Ser-1394 dephosphorylation by PP1 in vitro and (3) an increase in 14-3-3 association after PP1 inactivation in living cells. These results suggest that PP1 can modulate the downstream Ron signalling generated by MSP via Akt/PKB and 14-3-3 binding. This is the first report on ligand-regulated association of PP1 with a growth factor receptor.
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December 2003
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Research Article|
December 15 2003
Protein phosphatase 1 binds to phospho-Ser-1394 of the macrophage-stimulating protein receptor
Massimo M. SANTORO;
Massimo M. SANTORO
*Department of Medical Sciences, University of Piemonte Orientale ‘A. Avogadro’, 28100 Novara, Italy
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Giovanni GAUDINO;
Giovanni GAUDINO
*Department of Medical Sciences, University of Piemonte Orientale ‘A. Avogadro’, 28100 Novara, Italy
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Emma VILLA-MORUZZI
Emma VILLA-MORUZZI
1
†Department of Experimental Pathology, University of Pisa, via Roma 55, 56126 Pisa, Italy
1To whom correspondence should be addressed (e-mail villa@biomed.unipi.it).
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Publisher: Portland Press Ltd
Received:
March 12 2003
Revision Received:
September 15 2003
Accepted:
September 24 2003
Accepted Manuscript online:
September 24 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 376 (3): 587–594.
Article history
Received:
March 12 2003
Revision Received:
September 15 2003
Accepted:
September 24 2003
Accepted Manuscript online:
September 24 2003
Citation
Massimo M. SANTORO, Giovanni GAUDINO, Emma VILLA-MORUZZI; Protein phosphatase 1 binds to phospho-Ser-1394 of the macrophage-stimulating protein receptor. Biochem J 15 December 2003; 376 (3): 587–594. doi: https://doi.org/10.1042/bj20030391
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