Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis (original) (raw)
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MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer
Cancer Research, 2013
Cancers are initiated as a result of changes that occur in the genome. Identification of gains and losses in the structure and expression of tumor-suppressor genes and oncogenes lies at the root of the understanding of cancer cell biology. Here, we show that the mitogen–activated protein kinase (MAPK) MKK3 suppresses the growth of breast cancer, in which it varies in copy number. A pervasive loss of MKK3 gene copy number in patients with breast cancer is associated with an impairment of MKK3 expression and protein level in malignant tissues. To assess the functional role of MKK3 in breast cancer, we showed in an animal model that MKK3 activity is required for suppression of tumor growth. Active MKK3 enhanced expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p27Kip1, leading to increased cell-cycle arrest in G1 phase of the cell cycle. Our results reveal the functional significance of MKK3 as a tumor suppressor and improve understanding of the dynamic role of the ...
Role of MAP kinase in tumor progression and invasion
Cancer metastasis reviews, 2003
Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is a frequent event in tumorigenesis. MAPKs have been implicated in cell migration, proteinase-induction, regulation of apoptosis, and angiogenesis, events that are essential for successful completion of metastasis. In this review, we discuss the potential role that MAPKs play in metastasis by regulating cell migration, proteinase-induction and apoptosis.
Role of MAP kinase in tumor progression and invasion : Protein kinases
Cancer Metastasis Reviews, 2003
Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is a frequent event in tumorigenesis. MAPKs have been implicated in cell migration, proteinaseinduction, regulation of apoptosis, and angiogenesis, events that are essential for successful completion of metastasis. In this review, we discuss the potential role that MAPKs play in metastasis by regulating cell migration, proteinase-induction and apoptosis.
Cancer Research, 2009
Specific inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We used a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth inhibition by small-molecule MEK inhibitors. Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in response to MEK inhibition through a negative MEK-epidermal growth factor receptor-PI3K feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3K produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies. [Cancer Res 2009;69(2):565-72]
Expression of Novel Kinase MAP3K19 in Various Cancers and Survival Correlations
Frontiers in Bioscience-Landmark
Mitogen Activated Protein (MAP) kinases are a category of serine/threonine kinases that have been demonstrated to regulate intracellular events including stress responses, developmental processes, and cancer progression Although many MAP kinases have been extensively studied in various disease processes, MAP3K19 is an understudied kinase whose activities have been linked to lung disease and fibroblast development. In this manuscript, we use bioinformatics databases starBase, GEPIA, and KMPlotter, to establish baseline expressions of MAP3K19 in different tissue types and its correlation with patient survival in different cancers.
MAP3K1: Genomic Alterations in Cancer and Function in Promoting Cell Survival or Apoptosis
Genes & cancer, 2013
MAP3K1 is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family of serine/threonine kinases. MAP3K1 regulates JNK activation and is unique among human kinases in that it also encodes an E3 ligase domain that ubiquitylates c-Jun and ERK1/2. Full length MAP3K1 regulates cell migration and contributes to pro-survival signaling while its caspase 3-mediated cleavage generates a C-terminal kinase domain that promotes apoptosis. The critical function of MAP3K1 in cell fate decisions suggests that it may be a target for deregulation in cancer. Recent large-scale genomic studies have revealed that MAP3K1 copy number loss and somatic missense or nonsense mutations are observed in a significant number of different cancers, being most prominent in luminal breast cancer. The alteration of MAP3K1 in diverse cancer types demonstrates the importance of defining phenotypes for possible therapeutic targeting of tumor cell vulnerabilities created when MAP3K1 function is lost or...
Translational Oncology
INTRODUCTION: While mutations in PIK3CA are most frequently (45%) detected in luminal breast cancer, downstream PI3K/AKT/mTOR pathway activation is predominantly observed in the basal subtype. The aim was to identify proteins activated in PIK3CA mutated luminal breast cancer and the clinical relevance of such a protein in breast cancer patients. MATERIALS AND METHODS: Expression levels of 171 signaling pathway (phospho-)proteins established by The Cancer Genome Atlas (TCGA) using reverse phase protein arrays (RPPA) were in silico examined in 361 breast cancers for their relation with PIK3CA status. MAPK1/3 phosphorylation was evaluated with immunohistochemistry on tissue microarrays (TMA) containing 721 primary breast cancer core biopsies to explore the relationship with metastasis-free survival. RESULTS: In silico analyses revealed increased phosphorylation of MAPK1/3, p38 and YAP, and decreased expression of p70S6K and 4E-BP1 in PIK3CA mutated compared to wild-type luminal breast cancer. Augmented MAPK1/3 phosphorylation was most significant, i.e. in luminal A for both PIK3CA exon 9 and 20 mutations and in luminal B for exon 9 mutations. In 290 adjuvant systemic therapy naïve lymph node negative (LNN) breast cancer patients with luminal cancer, high MAPK phosphorylation in nuclei (HR = 0.49; 95% CI, 0.25-0.95; P = .036) and in tumor cells (HR = 0.37; 95% CI, 0.18-0.79; P = .010) was related with favorable metastasis-free survival in multivariate analyses including traditional prognostic factors. CONCLUSION: Enhanced MAPK1/3 phosphorylation in luminal breast cancer is related to PIK3CA exon-specific mutations and correlated with favorable prognosis especially when located in the nuclei of tumor cells.
F1000 - Post-publication peer review of the biomedical literature, 2000
Mitogen-activated protein kinases (MAPKs) are key mediators of evolutionarily conserved signaling networks that play an essential role in multiple aspects of cell physiology. 1,2 Activated by diverse stimuli, these signaling networks involve 3 sequential phosphorylation steps from MAPK kinase kinases (MAP3Ks, MEK kinases, or MKKKs) to MAPK kinases (MAP2Ks, MEK, or MKKs) to MAPKs. MAPKs are categorized into 4 subfamilies, extracellular signal response kinase 1/2 (ERK1/2), extracellular signal response kinase 5 (ERK5), c-Jun NH2-terminal kinase (JNK) or stress-activated protein kinase (SAPK), and p38. Twenty MAP3Ks, 7 MAP2Ks, and 11 MAPKs constitute an integrated signaling network responding to diverse stimuli to control critical functions in virtually all cells. 3 MAP3K1 or MEKK1 (MEK kinase 1) is a 196-kDa serine-threonine kinase that belongs to the MAP3K family and the STE superfamily. 2,4 MAP3K1 was originally identified as the mammalian homolog of the yeast MAP3Ks Ste11 and Byr2 that function in pheromone responsive signaling. 5 In addition to the conserved kinase domain, MAP3K1 has several unique structural characteristics that mediate its specific activities compared with other MAP3Ks. Studies have demonstrated that MAP3K1 functions in cell survival, apoptosis, and cell motility/migration in multiple normal and tumor cell types. Genetic alterations in the MAP3K1 gene have been recently found in comprehensive genomic analyses of cancers. As discussed herein, the function of MAP3K1 in apoptosis suggests why it is deleted or mutated in specific cancers.