The cyclopentenone 15-deoxy-delta 12,14-prostaglandin J2 binds to and activates H-Ras.
The cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) induces cell proliferation and mitogen-activated protein kinase activation. Here, we describe that these effects are mediated by 15d-PGJ(2)-elicited H-Ras activation. We demonstrate that this pathway is specific for H-Ras through the formation of a covalent adduct of 15d-PGJ(2) with Cys-184 of H-Ras, but not with N-Ras or K-Ras. Mutation of C184 inhibited H-Ras modification and activation by 15d-PGJ(2), whereas serum-elicited stimulation was not affected. These results describe a mechanism for the activation of the Ras signaling pathway, which results from the chemical modification of H-Ras by formation of a covalent adduct with cyclopentenone prostaglandins.
Oliva
Jose Luis
JL
Unidad de Biologia Celular, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain.
Pérez-Sala
Dolores
D
Castrillo
Antonio
A
Martínez
Natalia
N
Cañada
F Javier
FJ
Boscá
Lisardo
L
Rojas
José M
JM
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D011994:Recombinant Proteins; D018631:ras Proteins; D003545:Cysteine; D015230:Prostaglandin D2