Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that are activated in response to a variety of external signals. Extracellular signal-regulated kinases (ERK) comprise one subclass of MAPKs that can be activated by various receptor tyrosine kinases, cytokine receptors, G proteins, and oncogene products through phosphorylation by MAPKs or ERK-activated protein kinase (MEK). On activation of the MAPK NSC23766 research buy cascade, ERK is phosphorylated by MEK on threonine and tyrosine residues and translocates from the cytoplasm

to nucleus, where ERK phosphorylates several nuclear targets, including transcription factors [9]. After stimulation, ERK is phosphorylated by MEK, from which it then dissociates. The MEK-mediated phosphorylation of ERK, especially

tyrosine phosphorylation, is prerequisite for the dissociation of ERK from MEK. Dissociated ERK then enters the nucleus by either passive diffusion or active transport mechanisms [9]. ERK is implicated in various cellular processes, including PND-1186 chemical structure proliferation, differentiation, apoptosis, and transformation. Raf kinase inhibitor protein (RKIP), also termed phosphatidylethanolamine binding protein (PEBP)-1, is a 20-25 kDa globular protein that belongs to the PEBP family, encompassing more than 400 members [10]. RKIP is supposed to bind to Raf-1 and inhibit Raf-1-mediated phosphorylation of MEK [11, 12]. As a modulator of signaling pathways, RKIP also affects various cellular processes [13]. Deviant control of the MAPK PKC inhibitor cascade has been implicated in the development of human neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as various types of human cancer. Many Ras and B-Raf mutations occur in human cancer [14]. The purpose of this study was to investigate the expression of phosphorylated medroxyprogesterone ERK (p-ERK) and its upstream regulating signals such as phosphorylated MEK (p-MEK) and RKIP in human gastric cancer and to evaluate relations of the expressions of these proteins to clinicopathological variables and outcomes.

Methods Patients February 2004 through December 2007 we studied 105 patients who underwent curative gastrectomy (R0) for primary gastric adenocarcinomas penetrating beyond the muscularis mucosa at the Department of Esophagogastric Surgery, Tokyo Medical and Dental University. This study was conducted due to Declaration of Helsinki [15], and approved by Institutional Review Board of the Tokyo Medical and Dental university. Each tumour was classified according to the tumour-node-metastasis (TNM) classification recommended by the Union for International Cancer Control (UICC). All patients were evaluated for recurrent disease by examinations of tumour markers or by diagnostic imaging, including computed tomography, ultrasonography, magnetic resonance imaging, and endoscopy, every 3-6 months. No patient received neoadjuvant therapy. The median follow-up time was 55 months (range, 37-84).