Ca(2+)/calmodulin-dependent protein kinase II promotes cell cycle progression by directly activating MEK1 and subsequently modulating p27 phosphorylation
Authors: Nan Li
Chunmei Wang
Xingguang Liu
Xuetao Cao
Yanan Wu
Journal: Journal of Biological Chemistry (2009)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Cell proliferation; MAPK; phosphatidylinositol 3'-kinase; protein kinase C; Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)
Affiliations: Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China. Electronic address: ., Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China.

Abstract:  Cell proliferation is regulated by integration of multiple pathways, such as MAPK, phosphatidylinositol 3'-kinase, protein kinase C, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) signaling, determining whether the cell proceeds into cell cycle progression. Recently, we have demonstrated that a novel endogenous CaMKII-inhibitory protein, hCaMKIINalpha, suppresses tumor growth by inducing cell cycle arrest via p27 stabilization, accompanied by MEK/ERK deactivation. The data indicate a potential link between Ca(2+)/CaMKII and other signaling pathways, such as MAPK signaling. However, the detailed mechanisms of cross-talks between these important pathways on cell cycle regulation have not been specified. Here we report that CaMKII, in colon adenocarcinoma cells, activates MEK/ERK, which is responsible for the phosphorylation and subsequent proteasomal degradation of p27, thus causing the promotion of the S-G(2)/M transition of cell cycle progression. Importantly, we found that CaMKII can bind to MEK1 and that active CaMKII directly phosphorylates MEK1 in vitro, which could be abrogated by CaMKII inhibitor. Besides, ERK2 can directly interact with and phosphorylate p27. This is the first demonstration that CaMKII interplays with MEK1 and regulates p27 phosphorylation in the cell cycle progression. These findings provide mechanistic evidence for the cross-talk between CaMKII and MAPK signaling, which converges in MEK/ERK activation in the regulation of cell cycle progression. 

Retracted: No

PubPeer comments:
 2020 Expression of Concern. https: www.jbc.org content 295 26 8879 The publisher of the Journal of Biological Chemistry is issuing an Expression of Concern to inform readers that credible concerns have been raised regarding some of the data and conclusions in the article listed above. The Journal of Biological Chemistry will provide additional information as it becomes available. , 
 Retraction on Jan 1, 2021, published online May 22, 2021 https: www.jbc.org article S0021-9258(21)00559-7 fulltext Withdrawal: Ca2+ calmodulin-dependent protein kinase II promotes cell cycle progression by directly activating MEK1 and subsequently modulating p27 phosphorylation This article has been withdrawn by the authors. The Journal states that Fig. 5B presented many similar repeating features in the background of the top two left immunoblots. The authors state that they disagree with the Journalu2019s findings. The authors state that this study was conducted more than 10 years ago. The age of the work and the lack of availability of data storage makes it difficult for the authors to retrieve the requested raw data. The authorsu2019 offer to replace the images in question with those from another experiment with the same conditions was declined by the Journal. The authors state that the above issues do not affect the interpretation of the data nor conclusions of this research study. The authors affirm that phosphorylation of p27 occurs by activation of the MEK ERK cascade reported in the article has been confirmed by other independent studies, and they have indicated that they plan to resubmit their findings elsewhere for publication. , 
 #2  The Journal states that Fig. 5B presented many similar repeating features in the background of the top two left immunoblots. I increased the contrast of Fig 5B but it is hard to see the similar repeating features. Sadly, the image available in the PDF is low-resolution. There are straight-edged discontinuities but these could plausibly be compression artefacts.  It may be that the problems are more evident in the PDF originally submitted by the authors, but to their discredit, the new publishers of JBC have deleted all those original PDFs from the journal archives. , 
 #3 I agree with the previous comment. Looking elsewhere in the paper, it seems that a possible credible concern could instead be raised about the band marked in purple below. Not identical, but substantially similar, to my eye. ***  ,