The Shp-1 and Shp-2, tyrosine phosphatases, are recruited on cell membrane in two distinct molecular complexes including Ret oncogenes.
The Shp-2 and Shp-1 non-transmembrane tyrosine phosphatases display different and even opposing effects on downstream signaling events initiated by Ret activation. By using rat pheochromocytoma-derived PC12 cells, here we studied the interactions of Shp-2 and Shp-1 with two activated mutants of Ret receptor, Ret(C634Y) and Ret(M918T). Each of these mutated receptors causes inheritance of distinct cancer syndromes, multiple endocrine neoplasia (MEN) type 2A and type 2B, respectively. We show that: (i) both Shp-1 and Shp-2 are associated to a multiprotein complex that includes Ret mutants; (ii) the Shp-1-Ret complexes are distinct from Shp-2-Ret complexes, and these complexes are differently distributed inside and outside lipid rafts; (iii) constitutively activated Ret proteins neither directly bind to nor are substrates of these phosphatases. Our results well support the evidence that Ret complexes within and outside rafts mediate distinct biological functions, and indicate that the presence of either Shps participates to determine such functions.
Incoronato
Mariarosaria
M
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II", Via S. Pansini 5, 80131, Naples, Italy.
D'Alessio
Amelia
A
Paladino
Simona
S
Zurzolo
Chiara
C
Carlomagno
Maria Stella
MS
Cerchia
Laura
L
de Franciscis
Vittorio
V
D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000201:enzymology* / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids / Q000737:chemistry; D021962:Membrane Microdomains / Q000378:metabolism*; D009154:Mutation; D017830:Octoxynol / Q000494:pharmacology; D016716:PC12 Cells; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D013395:Sucrose / Q000494:pharmacology
D003902:Detergents; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D011518:Proto-Oncogene Proteins; D013395:Sucrose; D017830:Octoxynol; D005982:Glutathione Transferase; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C495001:Ret protein, rat; D010744:Phosphoric Monoester Hydrolases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat