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β‐Arrestin‐kinase scaffolds: turn them on or turn them off?

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Abstract G‐protein‐coupled receptors (GPCRs) can signal through heterotrimeric G‐proteins or through β‐arrestins to elicit responses to a plethora of extracellular stimuli. While the mechanisms underlying G‐protein signaling is relatively well understood, the mechanisms by which β‐arrestins regulate the diverse set of proteins with which they associate remain unclear. Multi‐protein complexes are a common feature of β‐arrestin‐dependent signaling. The first two such complexes discovered were the mitogen‐activated kinases modules associated with extracellular regulated kinases (ERK1/2) and Jnk3. Subsequently a number of other kinases have been shown to undergo β‐arrestin‐dependent regulation, including Akt, phosphatidylinositol‐3kinase (PI3K), Lim‐domain‐containing kinase (LIMK), calcium calmodulin kinase II (CAMKII), and calcium calmodulin kinase kinase β (CAMKKβ). Some are positively and some negatively regulated by β‐arrestin association. One of the missing links to understanding these pathways is the molecular mechanisms by which the activity of these kinases is regulated. Do β‐arrestins merely serve as scaffolds to bring enzyme and substrate together or do they have a direct effect on the enzymatic activities of target kinases? Recent evidence suggests that both mechanisms are involved and that the mechanisms by which β‐arrestins regulate kinase activity varies with the target kinase. This review discusses recent advances in the field focusing on 5 kinases for which considerable mechanistic detail and specific sites of interaction have been elucidated. WIREs Syst Biol Med 2013, 5:231–241. doi: 10.1002/wsbm.1203 This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models

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Model for Ras‐independent Raf activation by β‐arrestins. Raf exists in an autoinhibited state in which the N‐terminal regulatory domain interacts with residues in the C‐terminal kinase domain. Upon activation by certain GPCRs, β‐arrestin recruits raf, along with MEK and ERK1/2 to the membrane. This may result in a conformational change in raf exposing the kinase domain such that it can phosphorylate MEK, which in turn phosphorylates and activates ERK1/2. This conformational change may also facilitate autophosphorylation of Raf which contributes to increased activity. This mechanism of activation is associated with membrane‐retained ERK1/2 and phosphorylation of nonnuclear targets.

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Model for activation of src by β‐arrestins. Inactive src exists in an autoinhibited state characterized by intramolecular interactions between an inhibitory C‐terminal phosphotyrosine and the SH2 domain, and between the SH3 domain and the polyproline linker region N‐terminal to the kinase domain. β‐Arrestin is known to bind to the SH3 domain of src via a its own polyproline‐rich stretch which may destabilize the intramolecular interactions exposing the kinase domain to facilitate phosphorylation in the catalytic domain and dephosphorylation of the C‐terminus. Active src can phosphorylate and recruit the adaptor proteins shc and Grb2 which then recruits and activates the ras‐GEF, sos/GPCRs that promote β‐arrestin/src‐dependent MAPK activation and formation of β‐arrestin/src complexes may promote activation of src.

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Model for activation of the Jnk3 cascade by β‐arrestins. β‐Arrestins constitutive interact with the Jnk3 cascade (Ask1/MKK4/Jnk3). Upon activation of some GPCRs, the module is recruited to the membrane and its activity is increased. This may involve a conformational change in β‐arrestins that brings the module components closer together to facilitate sequential phosphorylation. It may also involve a conformational change in Ask1 that promotes its activity.

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Model for Ras‐dependent Raf activation by β‐arrestins. β‐Arrestins scaffold src which is required for activation of ERK1/2 by some GPCRs. Association with β‐arrestins may lead to src activation which is known to recruit adaptor proteins Grb2 and Shc, both of which are primary targets of receptor tyrsosine kinases. Grb2 when bound to phosphor‐tyrosines activates the Ras‐Guanine exchange factor (GEF), SOS, which leads to Ras‐dependent activation of Raf. This mechanism for ERK1/2 activation is associated with dimerization of active ERK1/2, nuclear translocation and expression of immediate early genes. Src‐bound β‐arrestin may also associate with Raf to facilitate this cascade.

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Models of Systems Properties and Processes > Mechanistic Models
Biological Mechanisms > Cell Signaling

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