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Comment
. 2018 Sep 25;11(549):eaav1646.
doi: 10.1126/scisignal.aav1646.

Arrestins and G proteins in cellular signaling: The coin has two sides

Vsevolod V Gurevich  1 , Eugenia V Gurevich  2
Affiliations
Comment

Arrestins and G proteins in cellular signaling: The coin has two sides

Vsevolod V Gurevich et al. Sci Signal. .

Abstract

Several studies have suggested that arrestin-mediated signaling by GPCRs requires G protein activation; however, in this issue of Science Signaling, Luttrell et al. documented arrestin-dependent activation of ERK1/2 by a number of GPCRs. These studies do not contradict each other, but illustrate the complexity of cellular signaling that cannot and should not be reduced to simplistic models.

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Figures

Fig. 1.
Fig. 1.. Multiple pathways lead to MAPK activation.
MAPK cascades consist of three kinases, MAP3K, MAP2K, and MAPK, which sequentially activate their downstream targets by phosphorylation. Arrestins have not been reported to participate in MAP3K activation, which initiates the signaling in MAPK cascades. G proteins can be activated by GPCR-dependent and GPCR-independent mechanisms. MAP3Ks are activated by RTKs, integrins, and several G protein–dependent mechanisms. Only after MAP3K activation can various scaffolds, including free and GPCR-bound arrestins, help to transform this first push into the activation of the most downstream MAPKs that are experimentally monitored in most studies of biased signaling. Note that JNK1/2/3 pathways are activated not only by ASK1 (which is not only scaffolded by arrestin-3) but also by other MAP3Ks, including MEKK1 to MEKK4, MLK, DLK, Tpl-2, and TAO1-2, with the help of other scaffolds. Note that c-Raf (cellular rapidly accelerated fibrosarcoma), ASK1 (apoptosis signal–regulated kinase 1), and MEKK1 to MEKK4, MLK, DLK, Tpl-2, and TAO1-2 are MAP3Ks; MEK1/2 and MKK4/7 are MAP2Ks; and Ras, Rac, and Cdc42 are small (single subunit) G proteins. Black circles indicate phosphorylation. Empty circles represent the dephosphorylation that is necessary for activation. ECM, extracellular matrix; PM, plasma membrane; ARR2/3, arrestin-2 or -3.
See this image and copyright information in PMC

Comment on

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