MAP3K1: Genomic Alterations in Cancer and Function in Promoting Cell Survival or Apoptosis (original) (raw)
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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.
MAP3K Family Review and Correlations with Patient Survival Outcomes in Various Cancer Types
Frontiers in Bioscience-Landmark
The mitogen-activated protein kinase (MAPK) pathways are ubiquitous in cellular signaling and are essential for proper biological functions. Disruptions in this signaling axis can lead to diseases such as the development of cancer. In this review, we discuss members of the MAP3K family and correlate their mRNA expression levels to patient survival outcomes in different cancers. Furthermore, we highlight the importance of studying the MAP3K family due to their important roles in the larger, overall MAPK pathway, relationships with cancer progression, and the understudied status of these kinases.
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 ...
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.
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.
Cell research, 2018
Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings...
MAPK SIGNALLING PATHWAY: ROLE IN CANCER PATHOGENESIS
Cancer is one of the prime causes of death presently. In normal cells, the firmly regulated pathway relays extracellular signals from the cell membrane to nucleus through a cascade of phosphorylation events. The Mitogen-Activated Protein Kinase (MAPK) cascades are among the most thoroughly studied signal transduction systems and have been proven to participate in a diverse array of cellular programs consisting of cell differentiation, cell movement, cell division and cell death. Constitutive activation of the MAPK cascade is associated with the carcinogenesis and melanoma development because of activating mutations within the B-RAF and RAS genes or other genetic or epigenetic modifications in their components or upstream activation of cell-surface receptors (e. g., EGFR and Flt-3) and chimeric chromosomal translocations (e. g. BCR-ABL) leading to elevated signaling activity eliciting cellular proliferation, invasion, metastasis, migration, survival and angiogenesis. Even in the absence of apparent genetic mutations, MAPK pathway has been stated to be activated in over 50% of Acute Myelogenous Leukemia (AML) and acute lymphocytic leukemia. In this brief review, we are about to outline the current advances in understanding the regulation of Mitogen-activated protein kinase signaling system and how can we generate specificity.
Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis
Oncogene, 2012
Analysis of patient tumors suggests multiple MAP3kinases (MAP3Ks) are critical for growth and metastasis of cancer cells. MAP3Ks selectively control the activation of ERK1/2, JNK, p38 and ERK5 in response to receptor tyrosine kinases and GTPases. We used MDA-MB-231 cells because of their ability to metastasize from the breast fat pad to distant lymph nodes for an orthotopic xenograft model to screen the function of seven MAP3Ks in controlling tumor growth and metastasis. Stable shRNA knockdown was used to inhibit the expression of each of the seven MAP3Ks, which were selected for their differential regulation of the MAPK network. The screen identified two MAP3Ks, MEKK2 and MLK3, whose shRNA knockdown caused significant inhibition of both tumor growth and metastasis. Neither MEKK2 nor MLK3 have been previously shown to regulate tumor growth and metastasis in vivo. These results demonstrated that MAP3Ks, which differentially activate JNK, p38 and ERK5 are necessary for xenograft tumor growth and metastasis of MDA-MB-231 tumors. The requirement for MAP3Ks signaling through multiple MAPK pathways explains why several members of the MAPK network are activated in cancer. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Oncology Reports, 2017
Death-associated protein kinases (DAPKs) are members of the serine/threonine protein kinase family, which regulate cell death. Although DAPK3 has been implicated as a tumor suppressor, a recent study revealed an oncogenic role of DAPK3. However, the role of DAPK3 in non-small cell lung cancer (NSCLC) remains unclear. Therefore, we examined whether DAPK3 controls the progression of NSCLC using the NSCLC cell line, A549. We generated A549 cells stably expressing small hairpin RNA (shRNA) targeting DAPK3. In the A549 cells, the protein level of DAPK3 was decreased and the cell proliferation was inhibited. DAPK3 knockdown caused G 1 /G 0 cell cycle arrest as assessed by flow cytometric assay and reduced cyclin D1 expression in A549 cells. Phosphorylation of ERK and c-Myc, but not Akt and JNK, was inhibited by DAPK3 knockdown. Cell migration and invasion were also inhibited by DAPK3 knockdown as determined by a Boyden chamber assay and an invasion assay, respectively. Moreover, DAPK3 knockdown inhibited anchorage-independent cell growth as determined by soft-agar colony formation assay. In a mouse xenograft model, tumors derived from DAPK3knockdown cells exhibited reduced tumor growth. The present results demonstrated for the first time that DAPK3 controls proliferation, migration, invasion, soft-agar colony formation and tumor growth through activation of ERK/c-Myc signaling in A549 cells. These findings indicate that DAPK3 may be a novel target for the treatment of NSCLC.
Integrated Molecular Characterisation of the MAPK Pathways in Human Cancers
2020
The mitogen-activated protein kinase (MAPK) pathways are a crucial regulator of the cellular processes that fuel the malignant transformation of normal cells. The genetic underpinnings of molecular aberrations which lead to cancer involve mutations in and, transcription variations of, various MAPK pathway genes. Here, we use datasets of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We identify the subset of these genes within which mutations tend to be associated with the worst disease outcomes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in t...