p120-catenin in cancer – mechanisms, models and opportunities for intervention

Schackmann, Ron C.J.; Tenhagen, Milou; Ven, Robert A. H. van de; Derksen, Patrick W.B.

doi:10.1242/jcs.134411

Cited by 83 publications

(88 citation statements)

References 136 publications

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“…[22][23][24] Cell membrane-localized Kaiso is associated with p120 catenin bound to E-cadherin and previous studies have shown this complex regulates actin cytoskeletal structures. 28 In this study, we show that RhoH and Kaiso interact and co-localize after SDF-1 stimulation at actin-rich cell protrusion sites in Jurkat cells. SDF-1 is a chemokine known to induce directed cell migration in several haematopoietic cell populations, including lymphocytes and haematopoietic stem cells.…”

Section: Discussionsupporting

confidence: 52%

RhoH participates in a multi-protein complex with the zinc finger protein kaiso that regulates both cytoskeletal structures and chemokine-induced T cells

et al. 2016

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RhoH is a haematopoietic -specific, GTPase-deficient Rho GTPase that plays an essential role in T lymphocyte development and haematopoietic cell migration. RhoH is known to interact with ZAP70 in T cell receptor (TCR) signaling and antagonize Rac GTPase activity. To further elucidate the molecular mechanisms of RhoH in T cell function, we carried out in vivo biotinylation and mass spectrometry analysis to identify new RhoH-interacting proteins in Jurkat T cells. We indentified Kaiso by streptavidin capture and confirmed the interaction with RhoH by co-immunoprecipitation. Kaiso is a 95 kDa dual-specific Broad complex, Trantrak, Bric-a-brac/Pox virus, Zinc finger (POZ-ZF) transcription factor that has been shown to regulate both gene expression and p120 cateninassociated cell-cell adhesions. We further showed that RhoH, Kaiso and p120 catenin all co-localize at chemokine-induced actin-containing cell protrusion sites. Using RhoH knockdown we demonstrated that Kaiso localization depends on RhoH function. Similar to the effect of RhoH deficiency, Kaiso down-regulation led to altered cell migration and actin-polymerization in chemokine stimulated Jurkat cells. Interestingly, RhoH and Kaiso also co-localized to the nucleus in a time-dependent fashion after chemokine stimulation and with T cell receptor activation where RhoH is required for Kaiso localization. Based on these results and previous studies, we propose that extracellular microenvironment signals regulate RhoH and Kaiso to modulate actin-cytoskeleton structure and transcriptional activity during T cell migration.

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Section: Discussionsupporting

confidence: 52%

RhoH participates in a multi-protein complex with the zinc finger protein kaiso that regulates both cytoskeletal structures and chemokine-induced T cells

et al. 2016

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“…FMNL2 is one of the effector proteins of small GTPases, such as Cdc42, and was shown to regulate actin dynamics and cell morphology (Kuhn and Geyer, 2014). In addition to functioning as an important regulator of classic cadherins, p120 is a main regulator of Rho GTPase and thus has a prominent effect on actin dynamics and cell morphology (Schackmann et al, 2013). Whether phosphorylation by TNIK alters the ability of these substrates to regulate actin dynamics will require further studies with phosphoblocking and phosphomimetic mutants.…”

Section: Discussionmentioning

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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“…Although the function of p120ctn and its direct homologs in regulating the actin cytoskeleton via small RhoGTPases is well established (Wolf et al, 2006;Anastasiadis, 2007;Keil et al, 2007;Dohn et al, 2009;Schackmann et al, 2013), much less is known about the role of PKPs in organizing actin fi laments and regulating Rho-GTPases. Keratinocyte cell -cell adhesion and differentiation depends on calcium-mediated and calcium-sensing receptor-mediated RhoA-signaling (Tu & You, 2013).…”

Section: Rho-signalingmentioning

confidence: 99%

Plakophilins in Desmosomal Adhesion and Signaling

Hatzfeld

Wolf

Keil

2014

Cell Communication & Adhesion

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The regulation of adhesion and growth is important for epithelial function and dysfunction. β -catenin ( armadillo in Drosophila ) is the prototype of a multifunctional molecule that regulates cell adhesion via adherens junctions and cell signaling via LEF/TCF transcription factors. Desmosomal armadillo proteins comprise plakoglobin and the plakophilins 1, 2, and 3. These proteins are essential for building up the desmosome and linking the desmosomal cadherins to keratin fi laments. High expression of plakophilins in desmosomes correlates with strong intercellular cohesion and is essential for tissue integrity under mechanical stress. However, like β -catenin, these proteins have diverse non-desmosomal functions, for example, in regulating actin organization, protein synthesis, and growth control. In line with these functions, their de-regulated expression with up-as well as down-regulation has been connected to cancer and metastasis. Now, recent evidence sheds light on the post-translational regulation and provides an explanation for how de-regulation of plakophilins can contribute to cancer.

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p120-catenin in cancer – mechanisms, models and opportunities for intervention

Cited by 83 publications

References 136 publications

RhoH participates in a multi-protein complex with the zinc finger protein kaiso that regulates both cytoskeletal structures and chemokine-induced T cells

RhoH participates in a multi-protein complex with the zinc finger protein kaiso that regulates both cytoskeletal structures and chemokine-induced T cells

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

Plakophilins in Desmosomal Adhesion and Signaling

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