Although DISC1 is multifunctional, its role for neurite outgrowth has been substantially characterized for the past couple of years (Ozeki et al., 2003; Miyoshi et al., 2003; Kamiya et al., 2006). These studies indicated that DISC1 is involved in neurite outgrowth by more than one mechanism, such as interactions with NUDEL/NDEL1 and FEZ1.
These two papers from Kaibuchiís lab provide further understanding of how DISC1 is involved in neuronal outgrowth. Kaibuchiís group identified kinesin heavy chain of kinesin-1 as a novel interactor of DISC1. In their papers, a novel role for DISC1, to link kinesin-1 (microtubule-dependent and plus-end directed motor) to several cellular molecules, including NUDEL, LIS1, 14-3-3, and Grb2, is reported. DISC1 and kinesin-1 are, therefore, responsible to sort Grb2 to the distal part of axons where Grb2 functions as an adaptor and plays a role in NT-3-induced phosphorylation of ERK1/2. This mechanism well explains our previous work, led by Ryota Hashimoto, reporting that knockdown of DISC1 expression results in decreased levels of phosphorylation of ERK1/2 and Akt in primary cortical neurons (Hashimoto et al., 2006).
The interaction of DISC1 and kinesin-1 may also be interesting from the perspective of psychiatric genetics. First, the mechanism proposed in one of the papers (Taya et al., 2007) supports the notion that the C-terminal truncated DISC1 fragment—that occurs due to the balanced translocation in an extended Scottish family—functions as a dominant-negative. Second, the domain of DISC1 responsible for kinesin-1 is overlapped with the haplotype block region(s) that are positive in more than one association study of DISC1 and major mental illnesses.
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Two recent back-to-back papers, published this month in Journal of Neuroscience, highlight the value of protein-protein interactions in determining the biological role of a key schizophrenia risk factor, DISC1, in processes that are important for the proper development of neurons.
Key questions need to be addressed once having established a set of interactors for a given protein. First, where do these proteins interact on the target molecule? Second, do these interactions take place at the same time (i.e., do they form a complex)? Third, in what context do these interactions occur (temporal, tissue/cell compartment, signaling), and, fourth, are the biological processes of the interacting molecules affected/regulated by the protein of interest? The Kaibuchi lab, as exemplified in the works by Taya et al. and Shinoda et al., elegantly address some of these questions in the context of DISC1 interactions with Grb2, Nudel (NDEL1), 14-3-3ε, and kinesin-1. The key findings of these papers are as follows:
1. Identification of the interaction sites, or more importantly, which part of DISC1 is involved in particular processes, for example, that axon elongation is dependent on the N-terminal, but not the C-terminal portion of DISC1. This suggests that the DISC1 role in axon elongation is mediated by interactions with the N-terminal portion of DISC1 that could be competed for by the truncated protein in a dominant negative fashion (Camargo et al., 2007).
2. Although a protein may have many interacting partners, such as DISC1, these interactions may not occur at the same time. For example, DISC1 is able to form a ternary complex with kinesin-1 and NDEL1 or with kinesin-1 and Grb2. However, a ternary complex of DISC1-Grb2-NDEL1 is not possible as Grb2 and NDEL1 may be competing for the same interaction site on DISC1.
3. Protein interactions may occur in certain cellular compartments, in the case of DISC1, the cell body and the distal part of axons.
4. Neurotrophin-induced axon elongation requires DISC1.
These papers confirm some of the hypotheses raised by the interactions that we have recently derived for DISC1 and some of its interacting partners (see Camargo et al., 2007). From the DISC1 interactome, we concluded that DISC1 may affect key intracellular transport mechanisms, such as those regulated by kinesins, and that DISC1 may be downstream of neurotrophin receptors, via its interaction with SH3BP5, an adaptor protein, which we found to interact with SOS1, a guanine exchange factor that binds Grb2 and responds to signaling of neurotrophin receptors. These observations have been validated by Taya et al. and Shinoda et al. and demonstrate the value of the DISC1 interactome in understanding the role of DISC1, and as a valuable resource to the wider community.
The molecular function of DISC1, as defined by its structure, still remains elusive, requiring a more dedicated effort on this front. The good news is that, via its protein-protein interactions, significant progress on the role of DISC1 in key biological processes has been achieved, as illustrated by the work of different labs (Brandon et. al., 2004; Millar et al., 2005; Kamiya et al., 2005; and now by Shinoda et al. and Taya et al.).
View all comments by Luiz Miguel Camargo