Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINKβ

Hu, Yuanming; Leo, Cindy; Yu, Shichao; Huang, Betty; Wang, Hank; Shen, Mary; Luo, Ying; Daniel-Issakani, Sarkiz; Payan, Donald G.; Xu, Xiang

doi:10.1074/jbc.m404497200

Cited by 54 publications

(44 citation statements)

References 43 publications

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“…Indeed, misshapen-Nck-interacting (NIK)-related kinase (MINK) is a serine-threonine kinase that binds to Nck (28) and that has been shown to selectively connect the TCR to a signaling pathway leading to negative but not positive selection (29). The results shown in this study linking the conformational change in the TCR with negative selection are in keeping with the proposed role for MINK (29), and they suggest that association of Nck-MINK with the TCR during negative selection depends on a conformational change in the TCR complex.…”

Section: Discussionmentioning

confidence: 99%

A conformational change senses the strength of T cell receptor–ligand interaction during thymic selection

Risueño

Santen

Alarcón³

2006

Proc. Natl. Acad. Sci. U.S.A.

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T cell antigen receptor (TCR) triggering determines the fate of immature thymocytes. The affinity of the TCR for its endogenous peptide͞MHC ligands serves as a signal for positive or negative selection through mechanisms that are still little understood. We have used a conformation-specific antibody to demonstrate that recognition of TCR ligands that lead to negative selection induces a conformational change in the TCR in situ. In contrast, this conformational change is elicited in only a small percentage of immature thymocytes during positive selection. Using a TUNEL assay, we demonstrate that the conformational change in the TCR is strongly linked to activation of programmed cell death in conditions leading to negative selection. Furthermore, the few conformational change-positive thymocytes detected in conditions that preferably lead to positive selection are also TUNELpositive. Thus, the conformational change in the TCR may underlie the discrimination of ligands leading to positive and negative selection.signal transduction ͉ thymic differentiation ͉ negative selection T he T cell antigen receptor (TCR) complex is composed in most T cells of the ligand-binding TCR␣ and TCR␤ subunits and the signal-transducing CD3␥, CD3␦, CD3 , and CD3 (CD247) (1, 2). The differentiation of T cells is controlled by the transduction of pre-TCR and TCR signals. Differentiation of immature CD4 ϩ CD8 ϩ double-positive (DP) to mature CD4 ϩ or CD8 ϩ single-positive thymocytes is initiated when the TCR-␣␤ heterodimer engages the peptide͞MHC (pMHC) (2). A unique feature of the TCR is its ability to scan structurally similar pMHC ligands and transmit distinct biochemical signals depending on the strength of the ligand recognized (3, 4). In developing thymocytes, weak TCR ligands induce positive selection, and stronger ligands induce negative selection (5). However, mature T cells are tolerant to weak TCR ligands in the periphery, and they respond to strong ligands by activating a program of cell proliferation and cell differentiation. The differential responsiveness of immature and mature T cells to weak ligands constitutes the cornerstone of self-tolerance that is acquired in the thymus.Many studies have focused on how the TCR␣␤ heterodimer communicates ligand engagement to the CD3 subunits, how the CD3 subunits translate this information into a specific cellular response, and how the TCR complex discriminates between strong and weak ligands. The engagement of the TCR with a weak ligand in mature T cells results in a distinct pattern of intracellular signaling compared with that induced by a full-agonist peptide. For example, stimulation with a weak ligand induces only partial phosphorylation of the CD3 and CD3 chains and the recruitment, but not the phosphorylation, of the -associated protein of 70 kDa, ZAP70 (6, 7). Hence, weak ligands activate only a subset of the downstream signaling pathways that are activated by an agonist peptide (8). Weak ligands bind to the TCR with a lower affinity and a higher dissociation rate than full a...

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Section: Discussionmentioning

confidence: 99%

A conformational change senses the strength of T cell receptor–ligand interaction during thymic selection

Risueño

Santen

Alarcón³

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, the caspase-dependent MAP4Ks and MST1/2 activation may not be relevant to the Hippo pathway. A few MAP4Ks, including MAP4K1/4/6, are known to interact with NCK1 (noncatalytic region of tyrosine kinase adaptor protein 1), which is an adaptor protein containing Src homology 2 (SH2) and SH3 domains (Su et al 1997;Ling et al 1999Ling et al , 2001Hu et al 2004). NCK1 is located in the cytoplasm and is involved in Ras-GTPase activation by receptor tyrosine kinases (Ger et al 2011) as well as Rho-GTPase activation and actin cytoskeleton A proposed sequential phosphorylation model of LATS activation by MST.…”

Section: The Regulation Of Lats-activating Kinases Mst1/2 and Map4ksmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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“…MAP4K4 belongs to the mammalian STE20/MAP4K family. Recent studies have shown that MAP4K4 is associated with cell motility, rearrangement of the cytoskeleton, and cell growth (26)(27)(28). Downregulation of MAP4K4 prevents TNF-a-induced insulin resistance in human skeletal muscle (29), and suppresses systemic inflammation by targeting macrophages (30).…”

Section: Introductionmentioning

confidence: 99%

miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4

Zhao

Wang

Liu

et al. 2013

Molecular Cancer Therapeutics

139

110

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miRNAs are associated with various types of cancer due to their ability to affect expression of genes that modulate tumorigenesis. In this study, we explored the role of miR-141 in pancreatic cancer. The analysis of clinical characteristics showed that miR-141 was significantly downregulated in tissues and cell lines of pancreatic cancer. Moreover, the decreased miR-141 level was significantly associated with tumor size and TNM stage, as well as lymph node and distant metastasis. Meanwhile, both Kaplan-Meier and multivariate survival analysis showed decreased miR-141 were associated with overall survival. Overexpression of miR-141 in pancreatic cancer cells inhibited cell proliferation, clonogenicity, and invasion; induced G 1 arrest and apoptosis; and enhanced chemosensitivity. To understand how miR-141 mediates the phenotype of pancreatic cancer cells, a bioinformatics tool was used to identify MAP4K4 as a potential target of miR-141. The DualLuciferase reporter gene assay showed that miR-141 binds directly to the 3 0 -untranslated region (3 0 UTR) of MAP4K4 to inhibit MAP4K4 expression. Western blot and quantitative real-time PCR (qRT-PCR) analyses revealed that MAP4K4 expression was inversely correlated with miR-141 expression both in pancreatic cancer samples and cell lines. Knockdown of MAP4K4 inhibited cell proliferation, clonogenicity, and invasion, induced G 1 arrest and apoptosis, and enhanced chemosensitivity. In a nude mouse xenograft model, both overexpression of miR-141 and knockdown of MAP4K4 significantly repressed pancreatic cancer cell growth. Therefore, we conclude that miR-141 targets MAP4K4, acts as a tumor suppressor in pancreatic cancer cells, and may serve as a novel therapeutic agent for miRNA-based pancreatic cancer therapy. Mol Cancer Ther; 12(11); 2569-80. Ó2013 AACR.

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Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINKβ

Cited by 54 publications

References 43 publications

A conformational change senses the strength of T cell receptor–ligand interaction during thymic selection

A conformational change senses the strength of T cell receptor–ligand interaction during thymic selection

Mechanisms of Hippo pathway regulation

miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4

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