scholarly journals Progesterone receptors act as sensors for mitogenic protein kinases in breast cancer models

2009 ◽  
Vol 16 (2) ◽  
pp. 351-361 ◽  
Author(s):  
Gwen E Dressing ◽  
Christy R Hagan ◽  
Todd P Knutson ◽  
Andrea R Daniel ◽  
Carol A Lange
Keyword(s):  
Breast Cancer ◽  
Protein Kinases ◽  
Cell Cycle Progression ◽  
Progesterone Receptors ◽  
Cancer Cell Line ◽  
Mitogen Activated Protein Kinase ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Mitogen Activated Protein ◽  
Regulatory Input

Progesterone receptors (PR), members of the nuclear receptor superfamily, function as ligand-activated transcription factors and initiators of c-Src kinase and mitogen-activated protein kinase signaling. Bidirectional cross-talk between PR and mitogenic protein kinases results in changes in PR post-translational modification, leading to alterations in PR transcriptional activity and promoter selectivity. PR-induced rapid activation of cytoplasmic protein kinases insures precise regulatory input to downstream cellular processes that are dependent upon nuclear PR, such as cell-cycle progression, and pro-survival signaling. Here, we review interactions between PR and mitogenic protein kinases and discuss the consequences of specific post-translational modifications on PR action in breast cancer cell-line models.

scholarly journals ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma–lamin A complexes

2010 ◽  
Vol 191 (5) ◽  
pp. 967-979 ◽  
Author(s):  
Javier Rodríguez ◽  
Fernando Calvo ◽  
José M. González ◽  
Berta Casar ◽  
Vicente Andrés ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Map Kinases ◽  
Cellular Transformation ◽  
Mitogen Activated Protein Kinase ◽  
Lamin A ◽  
Cellular Processes ◽  
Cell Cycle Entry ◽  
Mitogen Activated Protein ◽  
Cycle Regulation

As orchestrators of essential cellular processes like proliferation, ERK1/2 mitogen-activated protein kinase signals impact on cell cycle regulation. A-type lamins are major constituents of the nuclear matrix that also control the cell cycle machinery by largely unknown mechanisms. In this paper, we disclose a functional liaison between ERK1/2 and lamin A whereby cell cycle progression is regulated. We demonstrate that lamin A serves as a mutually exclusive dock for ERK1/2 and the retinoblastoma (Rb) protein. Our results reveal that, immediately after their postactivation entrance in the nucleus, ERK1/2 dislodge Rb from its interaction with lamin A, thereby facilitating its rapid phosphorylation and consequently promoting E2F activation and cell cycle entry. Interestingly, these effects are independent of ERK1/2 kinase activity. We also show that cellular transformation and tumor cell proliferation are dependent on the balance between lamin A and nuclear ERK1/2 levels, which determines Rb accessibility for phosphorylation/inactivation.

Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

2013 ◽  
Vol 394 (9) ◽  
pp. 1115-1132 ◽  
Author(s):  
Ugo Moens ◽  
Sergiy Kostenko
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Domain ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Processes ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Apoptosis Gene ◽  
And Function

Abstract Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases.

scholarly journals Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

2020 ◽  
Vol 21 (17) ◽  
pp. 6102
Author(s):  
Galia Maik-Rachline ◽  
Lucia Lifshits ◽  
Rony Seger
Keyword(s):  
Rna Processing ◽  
Nuclear Export ◽  
Cell Cycle Progression ◽  
Nuclear Translocation ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Mitogen Activated Protein ◽  
Nuclear Targets ◽  
Intracellular Targets

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ′s substrates, concentrating mainly on the nuclear targets and their role in p38α/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases.

scholarly journals Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

2021 ◽  
Vol 22 (11) ◽  
pp. 6041
Author(s):  
Yoshitoshi Kasuya ◽  
Jun-Dal Kim ◽  
Masahiko Hatano ◽  
Koichiro Tatsumi ◽  
Shuichi Matsuda
Keyword(s):  
Pulmonary Fibrosis ◽  
Protein Kinases ◽  
Molecular Mechanisms ◽  
Alveolar Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Sequencing Data ◽  
Alveolar Epithelial ◽  
Cellular Processes ◽  
Mitogen Activated Protein ◽  
Fibrotic Lung Diseases

Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.

scholarly journals Transcriptional Hyperactivity of Human Progesterone Receptors Is Coupled to Their Ligand-Dependent Down-Regulation by Mitogen-Activated Protein Kinase-Dependent Phosphorylation of Serine 294

2001 ◽  
Vol 21 (18) ◽  
pp. 6122-6131 ◽  
Author(s):  
Tianjie Shen ◽  
Kathryn B. Horwitz ◽  
Carol A. Lange
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Steroid Hormone ◽  
Progesterone Receptors ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Cell Growth ◽  
Down Regulation ◽  
Breast Cancer Cell Growth ◽  
Protein Levels ◽  
Mitogen Activated Protein

ABSTRACT Breast cancers often exhibit elevated expression of tyrosine kinase growth factor receptors; these pathways influence breast cancer cell growth in part by targeting steroid hormone receptors, including progesterone receptors (PR). To mimic activation of molecules downstream of growth factor-initiated signaling pathways, we overexpressed mitogen-activated protein kinase (MAPK; also known as extracellular signal-regulated kinase) kinase kinase 1 (MEKK1) in T47D human breast cancer cells expressing the B isoform of PR. MEKK1 is a strong activator of p42 and p44 MAPKs. MEKK1 expression increased progestin-mediated transcription 8- to 10-fold above normal PR-driven transcription levels. This was dependent on the presence of a progesterone response element and functional PR. PR protein levels were unchanged by MEKK1 alone but were extensively down-regulated by MEKK1 plus the progestin R5020. MEKK1 expression resulted in phosphorylation of PR on Ser294, a MAPK consensus site known to mediate ligand-dependent PR degradation. MEK inhibitors blocked phosphorylation of Ser294 and attenuated PR transcriptional hyperactivity in response to MEKK1 plus R5020; stabilization of PR by inhibition of the 26S proteasome produced similar results. T47D cells stably expressing mutant S294A PR, in which serine 294 is replaced by alanine, fail to undergo ligand-dependent down-regulation and are resistant to MEKK1-plus-R5020-induced transcriptional synergy but respond to progestins alone. Similarly, c-myc protein levels are synergistically increased by epidermal growth factor and R5020 in cells expressing wild-type PR, but not S294A PR. Thus, highly stable mutant PR are functional in response to progestins but are incapable of cross talk with MAPK-driven pathways. These studies demonstrate a paradoxical coupling between steroid receptor down-regulation and transcriptional hyperactivity. They also suggest a link between phosphorylation of PR by MAPKs in response to peptide growth factor signaling and steroid hormone control of breast cancer cell growth.

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