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MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Universidad Autónoma, 28049 Madrid, Spain.
Abstract:
The MEK5-extracellular signal-regulated kinase (ERK5) tandem is a novel mitogen-activated protein kinase cassette critically involved in mitogenic activation by the epidermal growth factor (EGF). The atypical protein kinase C isoforms (aPKCs) have been shown to be required for cell growth and proliferation and have been reported to interact with the adapter protein p62 through a short stretch of acidic amino acids termed the aPKC interaction domain. This region is also present in MEK5, suggesting that it may be an aPKC-binding partner. Here we demonstrate that the aPKCs interact in an EGF-inducible manner with MEK5 and that this interaction is required and sufficient for the activation of MEK5 in response to EGF. Consistent with the role of the aPKCs in the MEK5-ERK5 pathway, we show that zetaPKC and lambda/iotaPKC activate the Jun promoter through the MEF2C element, a well-established target of ERK5. From all these results, we conclude that MEK5 is a critical target of the aPKCs during mitogenic signaling.
Insights
Atypical protein kinase Cs (aPKCs) interact with MEK5 in response to epidermal growth factor (EGF), activating the MEK5-ERK5 pathway. This interaction is crucial for cell proliferation signaling.
Area of Science:
- Cellular signaling
- Molecular biology
- Biochemistry
Background:
- The MEK5-ERK5 pathway is vital for mitogenic activation by epidermal growth factor (EGF).
- Atypical protein kinase Cs (aPKCs) are essential for cell growth and proliferation and interact with p62 via an aPKC interaction domain.
- MEK5 possesses a similar domain, suggesting a potential interaction with aPKCs.
Purpose of the Study:
- To investigate the interaction between aPKCs and MEK5 in response to EGF.
- To determine the role of this interaction in MEK5 activation and downstream signaling.
- To elucidate the significance of MEK5 as a target in aPKC-mediated mitogenic signaling.
Main Methods:
- Co-immunoprecipitation assays to detect protein interactions.
- Western blotting to assess protein activation.
- Reporter gene assays (e.g., Jun promoter activation) to evaluate pathway activity.
Main Results:
- Demonstrated an EGF-inducible interaction between aPKCs and MEK5.
- Showed this interaction is necessary and sufficient for MEK5 activation by EGF.
- Confirmed that zetaPKC and lambda/iotaPKC activate the Jun promoter via the MEK5-ERK5 pathway's MEF2C element.
Conclusions:
- MEK5 is a critical target of aPKCs in the context of EGF-induced mitogenic signaling.
- The aPKC-MEK5 interaction is a key regulatory step in the MEK5-ERK5 pathway.
- This finding provides new insights into the mechanisms controlling cell proliferation.