scholarly journals Large tumor suppressor 2, LATS2, activates JNK in a kinase-independent mechanism through ASK1

2018 ◽  
Vol 10 (6) ◽  
pp. 549-558 ◽  
Author(s):  
Lauren Rusnak ◽  
Cong Tang ◽  
Qi Qi ◽  
Xiulei Mo ◽  
Haian Fu
Keyword(s):  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Protein Interactions ◽  
Cellular Response ◽  
Regulatory System ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Hippo Signaling ◽  
Large Tumor ◽  
Large Tumor Suppressor

Abstract Apoptosis signal-regulating kinase 1 (ASK1) is an important mediator of the cell stress response pathways. Because of its central role in regulating cell death, the activity of ASK1 is tightly regulated by protein–protein interactions and post-translational modifications. Deregulation of ASK1 activity has been linked to human diseases, such as neurological disorders and cancer. Here we describe the identification and characterization of large tumor suppressor 2 (LATS2) as a novel binding partner for ASK1. LATS2 is a core kinase in the Hippo signaling pathway and is commonly downregulated in cancer. We found that LATS2 interacts with ASK1 and increases ASK1-mediated signaling to promote apoptosis and activate the JNK mitogen-activated protein kinase (MAPK). This change in MAPK signaling is dependent on the catalytic activity of ASK1 but does not require LATS2 kinase activity. This work identifies a novel role for LATS2 as a positive regulator of the ASK1–MKK–JNK signaling pathway and establishes a kinase-independent function of LATS2 that may be part of the intricate regulatory system for cellular response to diverse stress signals.

scholarly journals MicroRNA miR-4709-3p targets Large Tumor Suppressor Kinase 2 (LATS2) and induces obstructive renal fibrosis through Hippo signaling

Bioengineered ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 12357-12371
Author(s):  
Zexiang Jiang ◽  
Weiping Xia ◽  
Guoyu Dai ◽  
Bo Zhang ◽  
Yang Li ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Renal Fibrosis ◽  
Hippo Signaling ◽  
Large Tumor ◽  
Large Tumor Suppressor

scholarly journals VRK2 Inhibits Mitogen-Activated Protein Kinase Signaling and Inversely Correlates with ErbB2 in Human Breast Cancer

2010 ◽  
Vol 30 (19) ◽  
pp. 4687-4697 ◽  
Author(s):  
Isabel F. Fernández ◽  
Sandra Blanco ◽  
José Lozano ◽  
Pedro A. Lazo
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Protein Interactions ◽  
Human Cancer ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Human Breast ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein

ABSTRACT The epidermal growth factor (EGF)-ErbB-mitogen-activated protein kinase (MAPK) transcription signaling pathway is altered in many types of carcinomas, and this pathway can be regulated by new protein-protein interactions. Vaccinia-related kinase (VRK) proteins are Ser-Thr kinases that regulate several signal transduction pathways. In this work, we study the effect of VRK2 on MAPK signaling using breast cancer as a model. High levels of VRK2 inhibit EGF and ErbB2 activation of transcription by the serum response element (SRE). This effect is also detected in response to H-Ras(G12V) or B-Raf(V600E) oncogenes and is accompanied by a reduction in phosphorylated extracellular signal-regulated kinase (ERK) levels, p90RSK levels, and SRE-dependent transcription. Furthermore, VRK2 knockdown has the opposite effect, increasing the transcriptional response to stimulation with EGF and leading to increased levels of ERK phosphorylation. The molecular mechanism lies between MAPK/ERK kinase (MEK) and ERK, since MEK remains phosphorylated while ERK phosphorylation is blocked by VRK2A. This inhibition of the ERK signaling pathway is a consequence of a direct protein-protein interaction between VRK2A, MEK, and kinase suppressor of Ras 1 (KSR1). Identification of new correlations in human cancer can lead to a better understanding of the biology of individual tumors. ErbB2 and VRK2 protein levels were inversely correlated in 136 cases of human breast carcinoma. In ErbB2+ tumors, there is a significant reduction in the VRK2 level, suggesting a role for VRK2A in ErbB2-MAPK signaling. Thus, VRK2 downregulation in carcinomas permits signal transmission through the MEK-ERK pathway without affecting AKT signaling, causing a signal imbalance among pathways that contributes to the phenotype of breast cancer.

Macrophage-Derived Exosomal miR-31-5p Promotes Oral Squamous Cell Carcinoma Tumourigenesis Through the Large Tumor Suppressor 2-Mediated Hippo Signalling Pathway

2021 ◽  
Vol 17 (5) ◽  
pp. 822-837
Author(s):  
Yi Yuan ◽  
Zeyu Wang ◽  
Mengqi Chen ◽  
Yang Jing ◽  
Wei Shu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Tumor Suppressor ◽  
Oral Squamous Cell Carcinoma ◽  
M2 Macrophage ◽  
Hippo Signaling ◽  
M2 Macrophages ◽  
Large Tumor ◽  
Hippo Signaling Pathway ◽  
Exosomal Mirnas ◽  
Large Tumor Suppressor

Tumour-associated macrophages (TAMs) are thought to contribute to oral squamous cell carcinoma (OSCC) initiation and progression. However, the underlying mechanism through which TAMs foster OSCC progression is still unclear. This study intended to determine whether there are exclusively exosomal miRNAs-derived macrophages that are functionally necessary for OSCC progression. The phenotype of TAM recruitment in OSCC tissue samples was assessed, subsequently identifying the influence of M2 macrophages and exosomes derived from M2 macrophages on OSCC proliferation and tumorigenesis in vitro and in vivo. CD68 and CD163, the specific markers of M2 type macrophages, were upregulated in TAMs presented in intra-cancer tissues. M2 macrophages and M2 macrophage-derived exosomes (M2 exos) both can promote OSCC growth and tumorigenicity. An exosomal RNA-seq analysis was conducted to predict regulatory exosomal miRNAs related to OSCC growth, which determined miR-31-5p and LATS2 for subsequent experiments. Mechanistically, miR-31-5p was delivered to recipient OSCC cells through M2 exos and complementary pairing with the large tumor suppressor 2 (LATS2) coding sequence, thus suppressing the expression of LATS2 and inactivation the Hippo signaling pathway to support OSCC growth. Collectively, our findings demonstrate that M2 macrophage-derived exosomal miR- 31-5p can make tumor suppressor LATS2 gene inhibited and facilitate the progression of OSCC via inhibiting the Hippo signaling pathway, which possibly provides new targets for the molecular therapy of OSCC.

scholarly journals Bu Shen Zhu Yun Decoction Improves Endometrial Receptivity via VEGFR-2-Mediated Angiogenesis

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Li Li ◽  
Huabo Jiang ◽  
Xuecong Wei ◽  
Dandan Geng ◽  
Ming He ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Embryo Implantation ◽  
Mapk Signaling ◽  
Endometrial Receptivity ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
Nuclear Antigen ◽  
Vitro Fertilization

Vascular endothelial growth factor receptor-2 (VEGFR-2) regulates the mitogen-activated protein kinase (MAPK) signaling pathway and plays an important role in angiogenesis. Bu Shen Zhu Yun decoction (BSZYD) can improve endometrial receptivity and embryo implantation rates in patients undergoing in vitro fertilization. However, whether BSZYD improves endometrial receptivity via angiogenesis remains unclear. Here, we investigated the effects of BSZYD on the proliferation, migration, and angiogenesis of human endometrial microvascular endothelial cells (HEMECs) and found that BSZYD upregulated the expression of cyclin D1, matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen (PCNA) in HEMECs. Cell Counting Kit 8 assay, scratch-wound assay, and Tube Formation Assay results showed that BSZYD promoted the proliferation, migration, and angiogenesis of HEMECs. Western blot analysis results revealed the activation of the MAPK signaling pathway by BSZYD through the upregulation of VEGF and VEGFR-2 expression. Together, these findings highlight the novel mechanism underlying BSZYD-mediated improvement in endometrial receptivity through the MAPK signaling pathway.

scholarly journals Vaccinia-Related Kinase 2 Modulates the Stress Response to Hypoxia Mediated by TAK1

2007 ◽  
Vol 27 (20) ◽  
pp. 7273-7283 ◽  
Author(s):  
Sandra Blanco ◽  
Claudio Santos ◽  
Pedro A. Lazo
Keyword(s):  
Stress Response ◽  
Cellular Response ◽  
Mapk Signaling ◽  
Cellular Stress Response ◽  
Mitogen Activated Protein Kinase ◽  
Stable Complex ◽  
Intracellular Proteins ◽  
Mitogen Activated Protein ◽  
Jnk Activation ◽  
Protein Kinase Kinase

ABSTRACT Hypoxia represents a major stress that requires an immediate cellular response in which different signaling pathways participate. Hypoxia induces an increase in the activity of TAK1, an atypical mitogen-activated protein kinase kinase kinase (MAPKKK), which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C-terminal region, forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or the downregulation of AP1-dependent transcription. Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response.

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