MEK5/ERK5 Signaling Modulates Endothelial Cell Migration and Focal Contact Turnover

Institute of Molecular Virology (IMV), Center of Molecular Biology of Inflammation (ZMBE), and Interdisciplinary Center of Medical Research (IZKF), Universitaetsklinikum Muenster, 48149 Muenster, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2009; 284(37):24972-80. DOI: 10.1074/jbc.M109.042911
Source: PubMed


The formation of new blood vessels from pre-existing ones requires highly coordinated restructuring of endothelial cells (EC) and the surrounding extracellular matrix. Directed EC migration is a central step in this process and depends on cellular signaling cascades that initiate and control the structural rearrangements. On the basis of earlier findings that ERK5 deficiency in mouse EC results in massive defects in vessel architecture, we focused on the impact of the MEK5/ERK5 signaling pathway on EC migration. Using a retroviral gene transfer approach, we found that constitutive activation of MEK5/ERK5 signaling strongly inhibits EC migration and results in massive morphological changes. The area covered by spread EC was dramatically enlarged, accompanied by an increase in focal contacts and altered organization of actin filaments. Consequently, cells were more rigid and show reduced motility. This phenotype was most likely based on decreased focal contact turnover caused by reduced expression of p130Cas, a key player in directed cell migration. We demonstrate for the first time that ERK5 signaling not only is involved in EC survival and stress response but also controls migration and morphology of EC.

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    • "The role of ERK5 in cell migration remains elusive. While keratinocyte and vascular smooth muscle cell migrations were shown to be positively regulated [Izawa et al., 2007; Arnoux et al., 2008], hepatic and endothelial cell migrations [Pi et al., 2005; Rovida et al., 2008; Spiering et al., 2009] were negatively regulated by ERK5. Thus, cell migration regulation by ERK5 may be cell-type specific and/or environmentally sensitive. "
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    ABSTRACT: Members of Rho family GTPases including Cdc42 are known to play pivotal roles in cell migration. Cell migration is also known to be regulated by many protein kinases. Kinetworks KPSS 11.0 phospho-site screening of Cdc42-silenced Hs578T breast cancer cells revealed most dramatic change in ERK5 MAP kinase. In the present study, we set out to determine the relationship between Cdc42 and ERK5 and its significance in breast cancer cell migration and invasion. Specific siRNAs were used for knocking down Cdc42 or ERK5 in breast cancer cells. Increased ERK5 phosphorylation in breast cancer cells was achieved by infection of constitutively active MEK5 adenovirus. The cells were then subjected to cell migration or invasion assay without the presence of serum or any growth factor. We found that Cdc42 negatively regulated phosphorylation of ERK5, which in turn exhibited an inverse relationship with migration and invasiveness of breast cancer cells. To find out some in vivo relevance of the results of our in vitro experiments we also examined the expression of ERK5 in the breast cancer tissues and their adjacent normal control tissues by real-time RT-PCR and immunocytochemistry. ERK5 expression was found to be reduced in breast cancer tissues as compared with their adjacent uninvolved mammary tissues. Therefore, Cdc42 may promote breast cancer cell migration and invasion by inhibiting ERK5 phosphorylation and ERK5 expression may be inversely correlated with the progression of some breast tumors. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2015 · Journal of Cellular Biochemistry
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    • "The ERK5 signaling cascade is essential for the control of cellular proliferation (7) and is likely to be targeted during cell cycle progression (8,9) and tumorigenesis (10,11). In addition, the ERK5 cascade is involved in the management of cell differentiation (12,13), migration (14,15), neuronal survival rate (16), embryonic angiogenesis (17) and additional cellular functions (18–21). "
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    ABSTRACT: Mitogen-activated protein kinase kinase kinase 2 (MEKK2) is an important upstream mediator of the extracellular signal-regulated kinase 5 signaling cascade that is essential for a number of cellular functions, including mitogenesis, differentiation and oncogenic transformation. Using western blotting to examine MEKK2 expression in 16 cases of primary colorectal cancer (CRC) lesions with paired normal mucosa, it was identified that MEKK2 is highly expressed in CRC lesions compared with that of the normal mucosa. Immunohistochemistry of 24 normal mucosa, 24 adenoma and 96 adenocarcinoma colorectal specimens indicated that the expression of MEKK2 was significantly increased in the adenoma and carcinoma specimens compared with that of the normal mucosa cases (P<0.0001 for both). However, no significant differences were detected in MEKK2 expression between the carcinoma and adenoma specimens (P=0.85). Similarly, no correlations were identified between MEKK2 expression and clinicopathological features, including gender, age, body mass index, histological differentiation, depth of invasion, lymph node metastasis, UICC stage and K-ras mutations (P>0.05). The present study demonstrated that MEKK2 functions as a promotive factor in CRC.
    Full-text · Article · Nov 2013 · Oncology letters
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    • "This cascade was initially thought to respond to stress stimuli only, but was later shown to be essential also for mitogenesis [5], which could be mediated by its role in cell cycle progression [6], [7], and together with ERK2, in oncogenic transformation [8], [9]. In addition, the ERK5 cascade plays a role in the regulation of differentiation [10], [11], migration [12], [13], [14], neuronal survival [15], embryonic angiogenesis [16], serial assembly of sarcomeres [17], determination of cortical neuronal fate [18] and more [19], [20]. "
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    ABSTRACT: The ERK5 cascade is a MAPK pathway that transmits both mitogenic and stress signals, yet its mechanism of activation is not fully understood. Using intracellular calcium modifiers, we found that ERK5 activation by EGF is inhibited both by the depletion and elevation of intracellular calcium levels. This calcium effect was found to occur upstream of MEKK2, which is the MAP3K of the ERK5 cascade. Co-immunoprecipitation revealed that EGF increases MEKK2 binding to the adaptor protein Lad1, and this interaction was reduced by the intracellular calcium modifiers, indicating that a proper calcium concentration is required for the interactions and transmission of EGF signals to ERK5. In vitro binding assays revealed that the proper calcium concentration is required for a direct binding of MEKK2 to Lad1. The binding of these proteins is not affected by c-Src-mediated phosphorylation on Lad1, but slightly affects the Tyr phosphorylation of MEKK2, suggesting that the interaction with Lad1 is necessary for full Tyr phosphorylation of MEKK2. In addition, we found that changes in calcium levels affect the EGF-induced nuclear translocation of MEKK2 and thereby its effect on the nuclear ERK5 activity. Taken together, these findings suggest that calcium is required for EGF-induced ERK5 activation, and this effect is probably mediated by securing proper interaction of MEKK2 with the upstream adaptor protein Lad1.
    Full-text · Article · Sep 2010 · PLoS ONE
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