MAPK upstream kinase (MUK)-binding inhibitory protein, a negative regulator of MUK/dual leucine zipper-bearing kinase/leucine zipper protein kinase

Mitogen-activated protein kinase upstream kinase/dual leucine zipper-bearin g kinase/leucine-zipper protein kinase (MUK/DLK/ZPK) is a MAPKKK class prot ein kinase that induces JNK/SAPK activation. We report here a protein named MBIP that binds to MUK/DLK/ZPK. MUK-binding inhibitory protein (MBIP) cont ains two tandemly orientated leucine-zipper-like motifs with a cluster of b asic amino acids located between the two motifs. MBIP interacts with one of the two leucine-zipper-like motifs of MUK/DLK/ZPK and inhibits the activit y of MUK/DLK/ZPK to induce JNK/SAPK activation. Notably, no similar effect was observed with another JNK/SAPK-inducing MAPKKK, COT/Tp1-2, showing the specificity of MBIP action. Furthermore, the overexpression of MBIP partial ly inhibits the activation of JNK by 0.3 M sorbitol in 293T cells. Taken to gether, these observations indicate that MBIP can function as a regulator o f MUK/DLK/ZPK, a finding that may provide a clue to understanding the molec ular mechanism of JNK/SAPK activation by hyperosmotic stress.