Dynamic duo regulate microtubule plasticity

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Phosphorylation of the microtubule-destabilizing protein SCG10 by JNK1 is a key event in balancing microtubule stability in axons and dendrites.

Proteins of the c-Jun amino (N)-terminal kinase (JNK) family are important in the regulation of brain development and in maintaining the structural integrity of the cytoskeleton. However, the molecules that mediate the effects of JNKs in these events have yet to be identified. Now, Tararuk and colleagues, writing in the Journal of Cell Biology, have established that phosphorylation of the microtubule-destabilizing protein SCG10 by JNK1 is a key event in balancing microtubule stabilization and destabilization, as well as in the regulation of axon and dendrite growth.

To shed light on the role of JNK1 in maintenance of microtubule stability, the authors set out to identify the binding partners of JNK1. Members of the stathmin family of microtubule-destabilizing proteins, specifically SCG10, SCLIP, RB3 and RB3', formed strong binding interactions with JNK1. Phosphorylation of these proteins blocks their destabilizing activity, allowing axon and dendrite growth. To determine which of this family of proteins, if any, could mediate the effects of JNK1, the authors analysed the rate of phosphorylation of stathmin, SCG10 and SCLIP by JNK1 in vitro. SCG10 was found to be JNK1's preferred substrate in vivo.

After elucidating the SCG10 residues phosphorylated by JNK1 — Ser62 and Ser73 — the authors investigated the functional importance of this event on microtubule dynamics. Expression of a functionally active SCG10 mutant, in which both serine residues were substituted with alanine, led to a $sim$ 50% reduction in the level of microtubule recovery/stability, the same level of reduction achieved by blocking the activity of cytoplasmic JNK1. These results indicate that it is the co-ordinated action of SCG10 and JNK1 that regulates microtubule dynamics.

The expression patterns of active JNK and SCG10 in embryonic brain show considerable overlap, with both proteins being concentrated in cortical regions undergoing differentiation. A $sim$ 50% reduction in phosphorylation of SCG10 in the cortex of JNK1-deficient mice also suggests that JNK1 is active in the developing forebrain.

To investigate the potential role of SCG10 as a mediator of JNK regulation of neuronal shape in development, a process that requires tight control of microtubule stability, the authors expressed two mutant forms of SCG10 in cortical neurons. Neurons expressing the functionally active mutant that was not regulated by JNK1 had $sim$ 30% reduction in process length, which was attributed to decreases in both axonal and dendritic components. By contrast, those expressing a functionally inactive mutant that structurally mimicked the phosphorylated form of SCG10 had processes of expected length. These results suggest that phosphorylation of SCG10 by JNK1 controls SCG10 regulation of microtubule stability.

Understanding how JNKs and their molecular effectors mediate physiological responses in the brain has implications for the elucidation of mechanisms that underlie both development and disease. The characterization of SCG10 as a molecular effector of JNK1 is a significant advance, and it will be interesting to see what specific roles the other binding partners of JNK1 have in developmental events.

Samantha Barton

References

Tararuk, T. et al. JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length. J. Cell Biol. 173, 265–277 (2006) | Article | PubMed |