|This figure from the Yip et al. paper illustrates the contributions of specific stathmin serine residues phosphorylation to microtubule preservation during hyperosmotic stress (OS). Arrows point at cells with destabilized microtubule cytoskeleton product of serine-to-alanine substitutions.
Understanding the regulation of cytoskeleton organization is fundamental for the control of cell division, migration, proliferation and differentiation. Cytoskeleton dynamics play a role both in physiological processes and in diseases such as cancer. In their recent article in The Journal of Biological Chemistry, Yan Y. Yip and colleagues at the University of Melbourne revealed new details about the complex signaling processes that determine cytoskeleton reorganization in response to cell stress.
When cells are exposed to stresses, such as heat shock, osmotic or chemical stress, inflammatory cytokines, proteasome inhibition and hypoxia, physiological responses promote the reorganization of the cytoskeleton to maintain structural integrity.
Microtubular cytoskeleton dynamics are in part determined by a small protein known as stathmin, or oncoprotein 18. Stathmin sequesters two tubulin dimers, destabilizing microtubules. It can be phosphorylated in various serine residues in response to stress. These post-translational modifications reduce the stathmin-dependent inhibition of microtubule assembly, stabilizing microtubules and preserving cytoskeleton structure.
The regulation of stathmin function through phosphorylation is a complicated process. Multisite phosphorylation occurs and different residues get modified depending on the cellular and signaling context.
The authors confirmed that stathmin gets phosphorylated during hyperosmotic stress by c-Jun N-terminal kinase, or JNK, and cAMP-dependent protein kinase, or PKA. These post-translational modifications inhibit stathmin activity and preserve the integrity of microtubules.
These researchers found by mutagenesis that two residues, S38 and S63, are essential in the response to hyperosmotic stress and required to fully attenuate the inhibitory effects of stathmin.
S38 is phosphorylated by JNK early during the response to hyperosmotic stress, followed by PKA-dependent S63 phosphorylation. However, phosphorylation of stathmin in position S63 did not require prior S38 phosphorylation. Additionally, the authors proposed an interesting cross-talk between JNK and PKA in which JNK could possibly be involved in the downregulation of PKA activity during hyperosmotic stress.
These results highlight some of the complexities of cytoskeleton regulation and the functional interconnection between signaling pathways during cellular responses to stress.
Mariana Figuera-Losada (firstname.lastname@example.org
) is a postdoctoral fellow at the Johns Hopkins University.