MINK and TNIK Differentially Act on Rap2-Mediated Signal Transduction to Regulate Neuronal Structure and AMPA Receptor Function

Hussain, Natasha K.; Hsin, Honor; Huganir, Richard L.; Sheng, Morgan

doi:10.1523/jneurosci.4124-10.2010

Cited by 62 publications

(59 citation statements)

References 45 publications

(90 reference statements)

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“…Thus, our data suggest less synapticallylocalized PSD-95, which may induce AMPAR internalization and induction of LTD in the ACC (Kim et al, 2007). Additionally, Rap2, a member of the Ras family of GTPases, indirectly activates JNK (Figure 3), and Rap2-JNK interactions traffic AMPA receptors away from the synapse during LTD, or bidirectionally in an activity dependent manner (Hussain et al, 2010;Thomas et al, 2008;Zhu et al, 2005). Interestingly, Rap2 function is modulated by SynGAP, a Ras and Rap GTPase-activating-protein, by its C2 domain (Funk et al, 2009;Pena et al, 2008).…”

Section: Discussionmentioning

confidence: 72%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

127

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Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3 0 -5 0 -cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK-and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC ¼ 36, DLPFC ¼ 35) and a comparison (ACC ¼ 33, DLPFC ¼ 31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK-and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK-and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK-and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.

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Section: Discussionmentioning

confidence: 72%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

127

View full text Add to dashboard Cite

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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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“…These kinases have been previously shown to impact neuronal integrity. 12 Due to the fact that even an extremely selective MAP4K4 inhibitor would still harbor significant inhibitory activity against these two highly homologous kinases, we proceeded with a target profile lacking brain penetration.…”

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confidence: 99%

Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis

Ndubaku¹,

Crawford²,

Chen³

et al. 2015

ACS Med. Chem. Lett.

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Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structurebased design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.

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MINK and TNIK Differentially Act on Rap2-Mediated Signal Transduction to Regulate Neuronal Structure and AMPA Receptor Function

Cited by 62 publications

References 45 publications

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

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

Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis

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