MINK is a Rap2 effector for phosphorylation of the postsynaptic scaffold protein TANC1

Nonaka, Hideo; Takei, Kimiko; Umikawa, Masato; Oshiro, Minoru; Kuninaka, Kouichi; Bayarjargal, Maitsetseg; Asato, Tsuyoshi; Yamashiro, Yoshito; Uechi, Yukiko; Endo, Shogo; Suzuki, Tatsuo; Kariya, Ken-ichi

doi:10.1016/j.bbrc.2008.10.038

Cited by 42 publications

(33 citation statements)

References 19 publications

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“…TNIK is highly enriched in synaptosome and postsynaptic density fractions where it regulates the stability of postsynaptic density proteins (Nonaka et al, 2008;Hussain et al, 2010;Wang et al, 2011). Among its various binding partners, TNIK interacts with disrupted in schizophrenia 1, a multifunctional scaffold protein whose altered function is linked with psychiatric disorders including schizophrenia, depression, and bipolar disorder (Blackwood et al, 2001;Camargo et al, 2007;Brandon and Sawa, 2011).…”

Section: Introductionmentioning

confidence: 99%

Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK

Wang

Amato

Rubitski

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Traf2-and Nck-interacting kinase (TNIK) is a serine/threonine kinase highly expressed in the brain and enriched in the postsynaptic density of glutamatergic synapses in the mammalian brain. Accumulating genetic evidence and functional data have implicated TNIK as a risk factor for psychiatric disorders. However, the endogenous substrates of TNIK in neurons are unknown. Here, we describe a novel selective small molecule inhibitor of the TNIK kinase family. Using this inhibitor, we report the identification of endogenous neuronal TNIK substrates by immunoprecipitation with a phosphomotif antibody followed by mass spectrometry. Phosphorylation consensus sequences were defined by phosphopeptide sequence analysis. Among the identified substrates were members of the delta-catenin family including p120-catenin, d-catenin, and armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), each of which is linked to psychiatric or neurologic disorders. Using p120-catenin as a representative substrate, we show TNIK-induced p120-catenin phosphorylation in cells requires intact kinase activity and phosphorylation of TNIK at T181 and T187 in the activation loop. Addition of the small molecule TNIK inhibitor or knocking down TNIK by two shRNAs reduced endogenous p120-catenin phosphorylation in cells. Together, using a TNIK inhibitor and phosphomotif antibody, we identify endogenous substrates of TNIK in neurons, define consensus sequences for TNIK, and suggest signaling pathways by which TNIK influences synaptic development and function linked to psychiatric and neurologic disorders.

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Section: Introductionmentioning

confidence: 99%

Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK

Wang

Amato

Rubitski

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Recently, it has been shown that the TPR and coiled-coil domains of TANC1 bind MINK and TNIK kinases (Nonaka et al, 2008). MINK was originally isolated as a gene whose expression is upregulated during postnatal mouse cerebral development (Dan et al, 2000), and both MINK and TNIK proteins are components of the postsynaptic density (Peng et al, 2004;Collins et al, 2006).…”

Section: Functions Of Tanc Proteinsmentioning

confidence: 99%

“…More recently, TANC1 was shown to interact with MINK (Misshapen/NIKs-related kinase) and TNIK (Traf2-and Nckinteracting kinase), which belong to the STE20 family of mitogenactivated protein kinase kinase kinase kinases (MAP4Ks) (Nonaka et al, 2008). Interestingly, TANC1 is phosphorylated by MINK and TNIK, which act downstream of Rap2 (Taira et al, 2004;Nonaka et al, 2008), a Ras family small GTPase implicated in the negative regulation of dendritic spines and synaptic AMPA receptors (Pak et al, 2001;Pak and Sheng, 2003;Zhu et al, 2005;Fu et al, 2007;Ryu et al, 2008). Despite these interesting characteristics of TANC1 expressed in the brain, the functions of TANC proteins have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Dendritic Spines, Spatial Memory, and Embryonic Development by the TANC Family of PSD-95-Interacting Proteins

Han¹,

Nam²,

Li³

et al. 2010

J. Neurosci.

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PSD-95 (postsynaptic density-95) is thought to play important roles in the regulation of dendritic spines and excitatory synapses, but the underlying mechanisms have not been fully elucidated. TANC1 is a PSD-95-interacting synaptic protein that contains multiple domains for protein-protein interactions but whose function is not well understood. In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. Overexpression of TANC1 and TANC2 in cultured neurons increases the density of dendritic spines and excitatory synapses in a manner that requires the PDZ (PSD-95/Dlg/ZO-1)-binding C termini of TANC proteins. TANC1-deficient mice exhibit reduced spine density in the CA3 region of the hippocampus, but not in the CA1 or dentate gyrus regions, and show impaired spatial memory. TANC2 deficiency, however, causes embryonic lethality. These results suggest that TANC1 is important for dendritic spine maintenance and spatial memory, and implicate TANC2 in embryonic development.

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“…In addition, all Rap2 proteins, including Rap2B, require palmitoylation for the induction of the TNIK-mediated phenotype, which led to the suppression of proliferation of human embryonic kidney (HEK)293T cells in a previous study (47). Nonaka et al (43) confirmed that MINK and TNIK interact with a postsynaptic scaffold protein containing tetratricopeptide repeats, ankyrin repeats and a coiled-coil region, inducing its phosphorylation, which is enhanced by Rap2.…”

Section: Potential Downstream Effectors Of Rap2bmentioning

confidence: 94%

“…Collins et al (46) demonstrated that the effects of MAP4K4 on promoting cellular migration were mediated through JNK, independently of activator protein 1 (AP-1) activation and downstream transcription. MINK is highly expressed in the brain, and its interaction with Rap2 is GTP-dependent and requires the presence of phenylalanine at position 39 within the effector region of Rap2 (43). TNIK was observed to be activated by the palmitoylation-deficient mutant of mouse Rap2B, and Rap2B promoted the growth and development of tumor cells through the activation and interaction with TNIK (42).…”

Section: Potential Downstream Effectors Of Rap2bmentioning

confidence: 99%

Structure, functional regulation and signaling properties of Rap2B

Qu¹,

Huang²,

Di³

et al. 2016

Oncology Letters

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Abstract. The Ras family small guanosine 5'-triphosphate (GTP)-binding protein Rap2B is is a member of the Ras oncogene family and a novel target of p53 that regulates the p53-mediated pro-survival function of cells. The Rap2B protein shares ~90% homology with Rap2A, and its sequence is 70% identical to other members of the Rap family such as RaplA and RaplB. As a result, Rap2B has been theorized to have similar signaling effectors to the GTPase-binding protein Rap, which mediates various biological functions, including the regulation of sterile 20/mitogen-activated proteins. Since its identification in the early 1990s, Rap2B has elicited a considerable interest. Numerous studies indicate that Rap2B exerts specific biological functions, including binding and stimulating phospholipase C-ε and interferon-γ. In addition, downregulation of Rap2B affects the growth of melanoma cells. The present review summarizes the possible effectors and biological functions of Rap2B. Increasing evidence clearly supports the association between Rap2B function and tumor development. Therefore, it is conceivable that anticancer drugs targeting Rap2B may be generated as novel therapies against cancer.

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MINK is a Rap2 effector for phosphorylation of the postsynaptic scaffold protein TANC1

Cited by 42 publications

References 19 publications

Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK

Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK

Regulation of Dendritic Spines, Spatial Memory, and Embryonic Development by the TANC Family of PSD-95-Interacting Proteins

Structure, functional regulation and signaling properties of Rap2B

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