title: Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2.
abstract: JNK scaffold proteins bind JNK and upstream kinases to activate subsets of JNK and localize activated JNK to specific subcellular sites. We previously demonstrated that the dual specificity phosphatases (DSPs) MKP7 and M3/6 bind the scaffold JNK-interacting protein-1 (JIP-1) and inactivate the bound subset of JNK (1). The G protein-coupled receptor (GPCR) adaptor beta-arrestin 2 is also a JNK3 scaffold. It binds the upstream kinases ASK1 and MKK4 and couples stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic pool of JNK3. Here we report that MKP7 also binds beta-arrestin 2 via amino acids 394-443 of MKP7, the same region that interacts with JIP-1. This region of MKP7 interacts with beta-arrestin 2 at a central region near the JNK binding domain. MKP7 dephosphorylates JNK3 bound to beta-arrestin 2, either following activation by ASK1 overexpression or following AT1aR stimulation. Initial AT1aR stimulation causes a rapid (within 5 min) dissociation of MKP7 from beta-arrestin 2. MKP7 then reassociates with beta-arrestin 2 on endocytic vesicles 30-60 min after initial receptor stimulation. This dynamic interaction between phosphatase and scaffold permits signal transduction through a module that binds both positive and negative regulators.
authors.affiliation: Division of Infection and Immunity, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, United Kingdom.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Willoughby
authors.forename: Mary K
authors.initials: MK
authors.lastname: Collins
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D054637:Dual-Specificity Phosphatases; D006801:Humans; D007668:Kidney / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases; D010766:Phosphorylation; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048057:Mitogen-Activated Protein Kinase 10; D054639:Mitogen-Activated Protein Kinase Phosphatases; C439065:DUSP16 protein, human; D054637:Dual-Specificity Phosphatases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases