In metastatic cancer, high expression levels of vitronectin (VN) receptors (integrins), FAK, and ERK5 are reported. We hypothesized that integrin-mediated ERK5 activation via FAK may play a pivotal role in cell adhesion, motility, and metastasis. ERK5 and FAK phosphorylation when metastatic MDA-MB-231 and PC-3 cells were plated on VN was enhanced. Further experiments showed co-immunoprecipitation of integrins beta1, alpha V beta 3, or alpha V beta 5 with ERK5 and FAK. To gain better insight into the mechanism of ERK5, FAK, and VN receptors in cell adhesion and motility, we performed loss-of-function experiments using integrin blocking antibodies, and specific mutants of FAK and ERK5. Ectopic expression of dominant negative ERK5/AEF decreased ERK5 and FAK (Y397) phosphorylation, cell adhesion, and haptotactic motility (micromotion) on VN. Additionally, DN FAK expression attenuated ERK5 phosphorylation, cell adhesion, and motility. This study documents the novel finding that in breast and prostate cancer cells, ERK5 is a critical target of FAK in cell adhesion signaling. Using different cancer cells, our experiments unveil a novel mechanism by which VN receptors and FAK could promote cancer metastasis via ERK5 activation.
"Knockout studies have linked ERK5 to vascular and cardiac development  , and thus functional analysis of ERK5 in tumor cells has focused on the importance of ERK5-dependent gene expression in tumor vascularity and angiogenesis. Interestingly, Sawhney and colleagues found that ERK5 co-immunoprecipitates with integrins and promotes FAK autophosphorylation and consequent activation in invasive tumor cells , linking ERK5 to cell adhesion and migration. However, the signaling mechanisms that mediate ERK5 activity in these complexes were not defined. "
[Show abstract][Hide abstract] ABSTRACT: MEKK2 is a serine/threonine kinase that functions as a MAPKinase kinase kinase (MAP3K) to regulate activation of MAP kinases. We recently have demonstrated that ablation of MEKK2 expression in invasive breast tumor cells dramatically inhibits xenograft metastasis, but the mechanism by which MEKK2 influences metastasis-related tumor cell function is unknown. In this study, we investigate MEKK2 function and demonstrate that silencing MEKK2 expression in breast tumor cell significantly enhances cell spread area and focal adhesion stability while reducing cell migration. We show that cell attachment to the matrix proteins fibronectin or Matrigel induces MEKK2 activation and localization to focal adhesions. Further, we reveal that MEKK2 ablation enhances focal adhesion size and frequency, thereby linking MEKK2 function to focal adhesion stability. Finally, we show that MEKK2 knockdown inhibits fibronectin-induced ERK5 signaling and FAK autophosphorylation. Taken together, our results strongly support a role for MEKK2 as a regulator of signaling that modulates breast tumor cell spread area and migration through control of focal adhesion stability.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 05/2014; 1843(5). DOI:10.1016/j.bbamcr.2014.01.029 · 5.02 Impact Factor
"Focal adhesion kinase (FAK) is a key player in tumor formation and progression54,55,56. Recently, Zhu et al showed that PIKE-A is a novel binding partner of FAK, and PIKE-A enhances its kinase activity in response to growth factor stimulation57. "
[Show abstract][Hide abstract] ABSTRACT: Tumorigenesis is the process by which normal cells evolve the capacity to evade and overcome the constraints usually placed upon their growth and survival. To ensure the integrity of organs and tissues, the balance of cell proliferation and cell death is tightly maintained. The proteins controlling this balance are either considered oncogenes, which promote tumorigenesis, or tumor suppressors, which prevent tumorigenesis. Phosphoinositide 3-kinase enhancer (PIKE) is a family of GTP-binding proteins that possess anti-apoptotic functions and play an important role in the central nervous system. Notably, accumulating evidence suggests that PIKE is a proto-oncogene involved in tumor progression. The PIKE gene (CENTG1) is amplified in a variety of human cancers, leading to the resistance against apoptosis and the enhancement of invasion. In this review, we will summarize the functions of PIKE proteins in tumorigenesis and discuss their potential implications in cancer therapy.
"One used a two-hybrid screen with an upstream activator MEK5 as the bait; the other used a degenerate PCR strategy to clone novel MAPK [123, 124]. ERK5 is activated by growth factors , integrin engagement , and cell stress  and contributes to expression induction of Ap1 (cJun  and Fos ), MEF family group (e.g., MEF2C, a well-characterized target , and c-Myc  transcription factors). "
[Show abstract][Hide abstract] ABSTRACT: The three major mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK are signal transducers involved in a broad range of cell functions including survival, apoptosis, and cell differentiation. Whereas JNK and p38 have been generally linked to cell death and tumor suppression, ERK plays a prominent role in cell survival and tumor promotion, in response to a broad range of stimuli such as cytokines, growth factors, ultraviolet radiation, hypoxia, or pharmacological compounds. However, there is a growing body of evidence supporting that JNK and p38 also contribute to the development of a number of malignances. In this paper we focus on the involvement of the MAPK pathways in prostate cancer, including the less-known ERK5 pathway, as pro- or antitumor mediators, through their effects on apoptosis, survival, metastatic potential, and androgen-independent growth.
Banghe Zhu, Holly Robinson, Songlin Zhang, Grace Wu, Eva M Sevick-Muraca
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