Abstract
Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family. It harbors a kinase domain in the N-terminus and a long C-terminus extension. The C-terminus extension comprises a conserved in ERK3 and ERK4 (C34) region and a unique C-terminus tail, which was shown to be required for the interaction of ERK3 with the cytoskeletal protein septin 7. Recent studies have elucidated the role of ERK3 signaling in promoting the motility and invasiveness of cancer cells. However, little is known about the intramolecular regulation of the enzymatic activity and cellular functions of ERK3. In this study, we investigated the role of the elongated C-terminus extension in regulating ERK3 kinase activity and its ability to promote cancer cell migration and invasion. Our study revealed that the deletion of the C-terminus tail greatly diminishes the ability of ERK3 to promote the migration and invasion of lung cancer cells. We identified two molecular mechanisms underlying this effect. Firstly, the deletion of the C-terminus tail decreases the kinase activity of ERK3 towards substrates, including the oncogenic protein steroid receptor co-activator 3 (SRC-3), an important downstream target for ERK3 signaling in cancer. Secondly, in line with the previous finding that the C-terminus tail mediates the interaction of ERK3 with septin 7, we found that the depletion of septin 7 abolished the ability of ERK3 to promote migration, indicating that septin 7 acts as a downstream effector for ERK3-induced cancer cell migration. Taken together, the findings of this study advance our understanding of the molecular regulation of ERK3 signaling by unraveling the role of the C-terminus tail in regulating ERK3 kinase activity and functions in cancer cells. These findings provide useful insights for the development of therapeutic agents targeting ERK3 signaling in cancer.
Highlights
Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that mediate intracellular signaling and regulate various cellular processes
The first region of this C-terminus extension is highly conserved in Extracellular signal-regulated kinase 3 (ERK3) and ERK4, it is called the C34 domain, whereas the remaining C-terminal tail is unique to ERK3 and does not share similarity with known domains in other proteins
We investigated the effects of truncating regions in the C-terminus extension on the ability of ERK3 to promote cancer cell invasiveness, and on the in vitro kinase activity of ERK3
Summary
Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that mediate intracellular signaling and regulate various cellular processes. Based on their structures and activation pathways, they are classified into conventional and atypical MAPKs [1]. Conventional MAPKs include extracellular signal-regulated kinases 1/2 (ERK1/2), p38, and ERK5. ERK3 (MAPK6) has an elongated C-terminal extension that comprises about 400 amino acids. Downstream of the C34, there is an unusually long tail of 240 amino acids that does not share significant homology with any known functional domains or motifs. Other MAPKs that have an elongated C-terminal extension beyond their kinase domains are ERK4, ERK5, and ERK7. The deletion of the C-terminal domain of ERK7 reduces its kinase activity [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
