CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway.
CIN85 is a multi-adaptor protein involved in different cellular functions including the down-regulation of activated receptor tyrosine kinases and survival of neuronal cells. CIN85 contains three SH3 domains that specifically bind a unique proline-arginine motif (PxxxPR) found in several CIN85 effectors. In this report, we show that the MAP kinase kinase kinase MEKK4 is a new CIN85-interacting partner. This interaction is mediated by the engagement of the SH3 domains of CIN85 to three PxxxPR motifs located within MEKK4 sequence. By disrupting this interaction we demonstrated that CIN85 binding to MEKK4 enhances the activation of MKK6 and of the downstream p38 MAP kinase following oxidative stress and growth factor stimulation. CIN85 was also shown to regulate the activation of MEKK4 by GADD45 proteins and promote multi-ubiquitination of MEKK4. Taken together, these results indicate a novel role for CIN85 in the regulation of cellular stress response via the MAPK pathways.
Aissouni
Youssef
Y
INSERM, U.624, 13288 Marseille, France.
Zapart
Grzegorz
G
Iovanna
Juan L
JL
Dikic
Ivan
I
Soubeyran
Philippe
P
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D007668:Kidney; D048768:MAP Kinase Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C433810:SH3KBP1 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048768:MAP Kinase Kinase Kinase 4; C482779:MAP3K4 protein, human