Arrestin Binding Sites for the Non Receptor Partners

Selective targeting of arrestin interactions with individual non-receptor partners has a tremendous therapeutic potential. Arrestin functions affect a huge variety of signaling mechanisms (Lefkowitz and Shenoy 2005; Gurevich and Gurevich 2006a), some of which may underlie the pathology of multiple diseases. For example, increases in arrestin expression in the brain of MPTP-treated monkeys with Parkinsonian symptoms (Bezard et al. 2005) and human patients with Parkinson's disease-dementia combination (Bychkov et al. 2007) were recently reported. Many arrestin-binding proteins (c-Src, ASK1, JNK3, c-Raf-1, ERK1/2, Mdm2, iKBa, etc.) are key players in pro-survival and pro-apoptotic pathways, suggesting that arrestin-mediated signaling participates in "life-or-death" decisions in the cell. Thus, enhancing pro-survival signaling at the arrestin level has a potential to prevent the excessive cell death characteristic for neurodegenerative diseases, such as Parkinson's, Alzheimer's, and retinitis pigmentosa, whereas enhancing arrestin-dependent pro-apoptotic signaling may counteract the excessive proliferation characteristic for every form of cancer. Pro-survival or pro-apoptotic "branches" of arrestin-mediated signaling could be modulated by enhancing or inhibiting the binding of pro- or antiapoptotic proteins, which can be achieved using properly designed small molecules. In the cell, interference with any one of the signaling pathways would also influence alternative arrestin-dependent signaling mechanisms. In a simplistic example, selective blockade of ERK1/2 binding would shift the balance toward the activation of JNK3, attenuating proliferation or even inducing apoptosis. Similarly, the disruption of arrestin-JNK3 interaction would re-direct the signaling to ERK1/2 and promote cell survival.

However, to realize the full potential of selective channeling of arrestin-mediated signaling, the binding sites for various partners must be mapped on the arrestin molecule with high precision. These studies are urgently needed: at the moment only arrestin elements involved in the binding to receptors (Vishnivetskiy et al. 2004; Hanson et al. 2006b), clathrin and AP2 (Kim and Benovic 2002), microtubules (Hanson et al. 2006a, 2007b), and calmodulin (Wu et al. 2006) have been properly mapped. The interaction sites for the remaining >20 binding partners are identified very imprecisely or not at all. Another issue that urgently requires thorough investigation is the competition and/or possible cooperation between different partners. For example, receptor-bound arrestin is believed to scaffold at least two MAP kinase cascades, c-Raf-1->MEK1->ERK1/2 and ASK1->MKK4->JNK3. A unitary arrestin-receptor complex is too small to accommodate all these proteins simultaneously (Gurevich and Gurevich 2006b), which suggests that it scaffolds either one of these cascades or the other. If arrestin interactions with MAPKKK (c-Raf-1 or ASK1) and MAPK (ERK1/2 or JNK3) were independent, half of the complexes would contain wrong combinations of kinases and therefore be unproductive. It stands to reason that the binding of MAPKKKs and MAPKs is coordinated, so that the complexes preferentially contain combinations of ERK1/2 with c-Raf-1 and JNK3 with ASK1. Direct experiments with purified proteins are needed to test which partners compete for the limited "parking space" on receptor-bound arrestin and which partners cooperate to end up in the same complex. Although dimerization of receptors (Angers et al. 2002), each recruiting its own arrestin molecule (Hanson et al. 2007a), may relieve the "overcrowding" of signaling proteins, it is unlikely to solve this particular problem, as members of the same MAP kinase cascade must be properly positioned relative to each other for the scaffold to work.

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