Grb2 interaction with MEK-kinase 1 is involved in regulation of Jun-kinase activities in response to epidermal growth factor.
Epidermal growth factor (EGF) receptor was shown to be involved in the activation pathway of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) cascade not only by EGF, but also by UV radiation or osmotic stress. This paper describes a specific interaction between the COOH-terminal SH3 domain of Grb2 and the NH2-terminal regulatory domain of MEKK1 in ER22 cells overexpressing the EGF receptor. This interaction results in the formation of a constitutive complex between Grb2 and MEKK1 in both proliferating and resting cells. EGF stimulation causes this complex to be rapidly and transiently recruited by Shc proteins. The subsequent release of the Grb2-MEKK1 complex from Shc proteins correlates with JNK activation. Transfection of the NH2-terminal regulatory domain of MEKK1 specifically inhibits EGF-dependent JNK activation indicating that Grb2 is involved in MEKK1 activation. Thus, adaptor proteins have a new role in the regulation of the SAPK/JNK cascade after EGF stimulation.
Pomérance
M
M
Unité 486 INSERM, Transduction Hormonale et Régulation Cellulaire, Faculté de Pharmacie, 92296 Châtenay-Malabry, France.
Multon
M C
MC
Parker
F
F
Venot
C
C
Blondeau
J P
JP
Tocqué
B
B
Schweighoffer
F
F
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D051380:GRB2 Adaptor Protein; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D015533:Transcriptional Activation; D014162:Transfection; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D011506:Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D015500:Chloramphenicol O-Acetyltransferase; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases