A study of the interaction between MAPKAP Kinase 5 / MK5 and DNAJB1
ForfatterLægreid, Kari Jenssen
The mitogen activated protein kinases (MAPK) are a large and diverse family of protein kinases, contributing to the cells ability to respond to external stimuli by relaying messages in a well orchestrated way until they reach their final destinations. This is achieved through successive phosphorylation events. One member of this large family is mitogen activated protein kinase activated protein kinase 5 (MAPKAPK5/MK5), which is activated by the upstream atypical MAPKs extracellular signal-regulated kinases 3 and 4 (ERK3 and ERK4), and possibly also the conventional MAPK p38MAPK. MK5 has been shown to be implicated in F-actin rearrangement through phosphorylation of heat shock protein 27 (HSP27), tumor suppression through at least two different pathways and cell cycle arrest in response to energy depletion. There has been done relatively little research on this protein, and few bona fide substrates for MK5 are known, although knowledge is emerging. One possible interaction partner for MK5 is DNAJB1, which has been shown to be phosphorylated by MK5 in vitro. DNAJB1 is a member of the heat shock protein 40 (HSP40) family/DNAJ family, which is a subunit of the much larger heat shock protein superfamily. Heat shock proteins mostly function as chaperones and co-chaperones in the cell, assisting in the maintenance of protein homeostasis, by refolding or degrading misfolded proteins. Conditions of stress in the cell can lead to increased levels of misfolded proteins, which in turn are thought to initiate the increased transcription of heat shock proteins observed in stressed cells. DNAJB1 mainly serves as a co-chaperone for heat shock protein 70, and has been implicated to play a role in various types of cancer and neurodegenerative disorders. In this study we demonstrated that MK5 phosphorylates DNAJB1 in vitro, and that Tyrosine residue 6 and Serine residues 149, 151 and 171 in DNAJB1 are in vitro phosphorylation sites for MK5. Our results also indicate that other phosphorylation sites may be present. Further experiments are needed to elucidate the in vivo potential of these phosphoacceptor sites. We also found that MK5 and DNAJB1 exist in complexes. This interaction proved hard to reproduce, indicating that it might be of a transient nature, or perhaps a product of non-physiological conditions. We also showed that both proteins localize mainly to the nucleus in resting cells, when ectopically expressed, and that DNAJB1 seems to downregulate the level or the transcriptional activity of MK5 when both proteins are ectopically expressed in the cell.
ForlagUniversitetet i Tromsø
University of Tromsø
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