Willoughby, Emma Alexandra; (2005) Interaction between dual specificity phosphatases and JNK scaffolds. Doctoral thesis , UCL (University College London).

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Abstract

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPKs) are activated by signals including environmental stresses, growth factors and hormones. In some pathways, scaffold proteins bind JNK and upstream kinases in order to activate subsets of JNK and localise them to specific subcellular sites. For example, the JNK-interacting protein (JIP) scaffold binds JNK, MKK7 and MLKs. The G protein coupled receptor (GPCR) adaptor protein ?-arrestin 2 has also recently been identified as a JNK scaffold, binding JNK3, ASK1 and indirectly MKK4. The work presented here shows that JNK specific dual specificity phosphatases MKP-7 and M3/6 bind to JIP-1 and -2 and that MKP-7 can also bind ?-arrestin 2. In both cases the phosphatases bind to the scaffolds independently of JNK, using the same region within their extended C terminal domains. MKP-7 can specifically dephosphorylate the ?-arrestin 2 bound subset of JNK3 either activated by ASK1 or in response to activation of the GPCR, angiotensin type 1a receptor (AT1aR). MKP-7 transiently dissociates from ?-arrestin 2 following AT1aR activation and over expression of ASK1. These results indicate that JIP-1 and ?-arrestin 2 modulate JNK signalling by binding JNK-specific kinases and phosphatases. The dynamic interaction between MKP-7 and ?-arrestin 2 suggests a possible mechanism by which a positive signal can be passed through a scaffold which binds both activating and inhibitory components.

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