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1.
Cell Mol Life Sci ; 81(1): 291, 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38970683

ABSTRACT

Plakophilin 4 (PKP4) is a component of cell-cell junctions that regulates intercellular adhesion and Rho-signaling during cytokinesis with an unknown function during epidermal differentiation. Here we show that keratinocytes lacking PKP4 fail to develop a cortical actin ring, preventing adherens junction maturation and generation of tissue tension. Instead, PKP4-depleted cells display increased stress fibers. PKP4-dependent RhoA localization at AJs was required to activate a RhoA-ROCK2-MLCK-MLC2 axis and organize actin into a cortical ring. AJ-associated PKP4 provided a scaffold for the Rho activator ARHGEF2 and the RhoA effectors MLCK and MLC2, facilitating the spatio-temporal activation of RhoA signaling at cell junctions to allow cortical ring formation and actomyosin contraction. In contrast, association of PKP4 with the Rho suppressor ARHGAP23 reduced ARHGAP23 binding to RhoA which prevented RhoA activation in the cytoplasm and stress fiber formation. These data identify PKP4 as an AJ component that transduces mechanical signals into cytoskeletal organization.


Subject(s)
Actins , Adherens Junctions , Plakophilins , rhoA GTP-Binding Protein , Plakophilins/metabolism , Plakophilins/genetics , rhoA GTP-Binding Protein/metabolism , Adherens Junctions/metabolism , Humans , Actins/metabolism , Keratinocytes/metabolism , Keratinocytes/cytology , GTPase-Activating Proteins/metabolism , GTPase-Activating Proteins/genetics , rho-Associated Kinases/metabolism , rho-Associated Kinases/genetics , Signal Transduction , Stress Fibers/metabolism , Cells, Cultured , Animals
2.
Cell Rep ; 42(1): 112031, 2023 01 31.
Article in English | MEDLINE | ID: mdl-36689330

ABSTRACT

Plakophilin 3 (PKP3) is a component of desmosomes and is frequently overexpressed in cancer. Using keratinocytes either lacking or overexpressing PKP3, we identify a signaling axis from ERK to the retinoblastoma (RB) protein and the E2F1 transcription factor that is controlled by PKP3. RB and E2F1 are key components controlling G1/S transition in the cell cycle. We show that PKP3 stimulates the activity of ERK and its target RSK1. This inhibits expression of the transcription factor RUNX3, a positive regulator of the CDK inhibitor CDKN1A/p21, which is also downregulated by PKP3. Elevated CDKN1A prevents RB phosphorylation and E2F1 target gene expression, leading to delayed S phase entry and reduced proliferation in PKP3-depleted cells. Elevated PKP3 expression not only increases ERK activity but also captures phosphorylated RB (phospho-RB) in the cytoplasm to promote E2F1 activity and cell-cycle progression. These data identify a mechanism by which PKP3 promotes proliferation and acts as an oncogene.


Subject(s)
Plakophilins , Retinoblastoma Protein , Animals , Mice , Cell Division , Cytoplasm/metabolism , E2F1 Transcription Factor/metabolism , ErbB Receptors/metabolism , Phosphorylation , Plakophilins/genetics , Plakophilins/metabolism , Retinoblastoma Protein/metabolism , S Phase , Signal Transduction
3.
Front Cell Dev Biol ; 9: 745670, 2021.
Article in English | MEDLINE | ID: mdl-34631720

ABSTRACT

Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural properties, which enable them to respond to context-dependent signals and transmit them to change cell behavior. Desmosome composition and size vary depending on tissue specific expression and differentiation state. Their constituent proteins are highly regulated by posttranslational modifications that control their function in the desmosome itself and in addition regulate a multitude of desmosome-independent functions. This review will summarize our current knowledge how signaling pathways that control epithelial shape, polarity and function regulate desmosomes and how desmosomal proteins transduce these signals to modulate cell behavior.

4.
J Cell Sci ; 133(8)2020 04 16.
Article in English | MEDLINE | ID: mdl-32122945

ABSTRACT

Desmosome remodeling is crucial for epidermal regeneration, differentiation and wound healing. It is mediated by adapting the composition, and by post-translational modifications, of constituent proteins. We have previously demonstrated in mouse suprabasal keratinocytes that plakophilin (PKP) 1 mediates strong adhesion, which is negatively regulated by insulin-like growth factor 1 (IGF1) signaling. The importance of PKP3 for epidermal adhesion is incompletely understood. Here, we identify a major role of epidermal growth factor (EGF), but not IGF1, signaling in PKP3 recruitment to the plasma membrane to facilitate desmosome assembly. We find that ribosomal S6 kinases (RSKs) associate with and phosphorylate PKP3, which promotes PKP3 association with desmosomes downstream of the EGF receptor. Knockdown of RSKs as well as mutation of an RSK phosphorylation site in PKP3 interfered with desmosome formation, maturation and adhesion. Our findings implicate a coordinate action of distinct growth factors in the control of adhesive properties of desmosomes through modulation of PKPs in a context-dependent manner.


Subject(s)
Desmosomes , Plakophilins , Animals , Cell Adhesion , Desmosomes/metabolism , Mice , Phosphorylation , Plakophilins/genetics , Plakophilins/metabolism , Ribosomal Protein S6 Kinases
5.
Cell Mol Life Sci ; 76(17): 3465-3476, 2019 Sep.
Article in English | MEDLINE | ID: mdl-30949721

ABSTRACT

Plakophilins (Pkp) are desmosomal plaque proteins crucial for desmosomal adhesion and participate in the regulation of desmosomal turnover and signaling. However, direct evidence that Pkps regulate clustering and molecular binding properties of desmosomal cadherins is missing. Here, keratinocytes lacking either Pkp1 or 3 in comparison to wild type (wt) keratinocytes were characterized with regard to their desmoglein (Dsg) 1- and 3-binding properties and their capability to induce Dsg3 clustering. As revealed by atomic force microscopy (AFM), both Pkp-deficient keratinocyte cell lines showed reduced membrane availability and binding frequency of Dsg1 and 3 at cell borders. Extracellular crosslinking and AFM cluster mapping demonstrated that Pkp1 but not Pkp3 is required for Dsg3 clustering. Accordingly, Dsg3 overexpression reconstituted cluster formation in Pkp3- but not Pkp1-deficient keratinocytes as shown by AFM and STED experiments. Taken together, these data demonstrate that both Pkp1 and 3 regulate Dsg membrane availability, whereas Pkp1 but not Pkp3 is required for Dsg3 clustering.


Subject(s)
Cell Adhesion , Desmoglein 1/metabolism , Desmoglein 3/metabolism , Plakophilins/genetics , Animals , Anisomycin/pharmacology , Cell Adhesion/drug effects , Cells, Cultured , Desmoglein 1/genetics , Desmoglein 3/genetics , Keratinocytes/cytology , Keratinocytes/metabolism , Mice , Microscopy, Atomic Force , Plakophilins/deficiency , Plakophilins/metabolism , Signal Transduction , p38 Mitogen-Activated Protein Kinases/metabolism
6.
J Cell Sci ; 131(10)2018 05 22.
Article in English | MEDLINE | ID: mdl-29678907

ABSTRACT

Desmosomes are essential for strong intercellular adhesion and are abundant in tissues exposed to mechanical strain. At the same time, desmosomes need to be dynamic to allow for remodeling of epithelia during differentiation or wound healing. Phosphorylation of desmosomal plaque proteins appears to be essential for desmosome dynamics. However, the mechanisms of how context-dependent post-translational modifications regulate desmosome formation, dynamics or stability are incompletely understood. Here, we show that growth factor signaling regulates the phosphorylation-dependent association of plakophilins 1 and 3 (PKP1 and PKP3) with 14-3-3 protein isoforms, and uncover unique and partially antagonistic functions of members of the 14-3-3 family in the regulation of desmosomes. 14-3-3γ associated primarily with cytoplasmic PKP1 phosphorylated at S155 and destabilized intercellular cohesion of keratinocytes by reducing its incorporation into desmosomes. In contrast, 14-3-3σ (also known as stratifin, encoded by SFN) interacted preferentially with S285-phosphorylated PKP3 to promote its accumulation at tricellular contact sites, leading to stable desmosomes. Taken together, our study identifies a new layer of regulation of intercellular adhesion by 14-3-3 proteins.


Subject(s)
14-3-3 Proteins/metabolism , Biomarkers, Tumor/metabolism , Desmosomes/metabolism , Exoribonucleases/metabolism , Plakophilins/metabolism , 14-3-3 Proteins/genetics , Biomarkers, Tumor/genetics , Cell Adhesion , Cytoplasm/metabolism , Desmosomes/genetics , Exoribonucleases/genetics , Humans , Keratinocytes/cytology , Keratinocytes/metabolism , Plakophilins/genetics
7.
J Cell Sci ; 130(19): 3374-3387, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28808088

ABSTRACT

We here report a novel function of the armadillo protein p0071 (also known as PKP4) during transport mediated by the KIF3 transport complex. Secretion of chromogranin A and matrix metallopeptidase 9 from pancreatic neuroendocrine tumor cells or pancreatic cancer cells, respectively, was substantially reduced following knockdown of p0071. Vesicle tracking indicated that there was impaired directional persistence of vesicle movement upon p0071 depletion. This suggests a disturbed balance between plus- and minus-end directed microtubule transport in cells lacking p0071. p0071 directly interacts with the KIF3 motor subunit KIF3B. Our data indicate that p0071 also interacts with the kinesin cargo adaptor protein KAP3 (also known as KIFAP3) acting as a stabilizing linker between KIF3B and its KAP3 cargo-binding entity. Thus, p0071 is required for directional vesicle movement and secretion of different KIF3-transported carriers, thereby regulating the transport of intracellular membrane vesicles along microtubules.


Subject(s)
Kinesins/metabolism , Plakophilins/metabolism , Secretory Vesicles/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , HEK293 Cells , HeLa Cells , Humans , Kinesins/genetics , Plakophilins/genetics , Protein Transport/physiology , Secretory Vesicles/genetics
8.
Article in English | MEDLINE | ID: mdl-28096266

ABSTRACT

Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing and in transducing mechanical forces between the plasma membrane and the actomyosin cytoskeleton, desmosomes and intermediate filaments (IFs) provide mechanical stability required to maintain tissue architecture and integrity when the tissues are exposed to mechanical stress. Desmosomes are essential for stable intercellular cohesion, whereas keratins determine cell mechanics but are not involved in generating tension. Here, we summarize the current knowledge of the role of IFs and desmosomes in tissue mechanics and discuss whether the desmosome-keratin scaffold might be actively involved in mechanosensing and in the conversion of chemical signals into mechanical strength.


Subject(s)
Cytoskeleton/metabolism , Desmosomes/metabolism , Intermediate Filaments/metabolism , Tissue Engineering/methods , Actin Cytoskeleton/metabolism , Actins/metabolism , Animals , Cell Adhesion , Cell Membrane/metabolism , Cytoskeletal Proteins/metabolism , Epithelium/metabolism , Humans , Keratinocytes/metabolism , Keratins/metabolism , Microtubules/metabolism , Protein Domains , Signal Transduction , Stress, Mechanical
9.
J Invest Dermatol ; 136(10): 2022-2029, 2016 10.
Article in English | MEDLINE | ID: mdl-27375112

ABSTRACT

Desmosomes are cell-cell adhesive structures essential for tissue integrity of the epidermis and the heart. Their constituents belong to multigene families giving rise to desmosomes of variable composition. So far, the functional significance of context-dependent composition in desmosome formation, dynamics, or stability during epidermal differentiation is incompletely understood. In this comparative study, we have uncovered unique and partially antagonistic functions of plakophilins 1 and 3 that are both expressed in the murine epidermis. These plakophilins differ in their localization patterns and kinetics during de novo desmosome formation and are regulated by distinct mechanisms. Moreover, plakophilin 3-containing desmosomes are more dynamic than desmosomes that contain predominantly plakophilin 1. Further, we show that Ca(2+)-independence of desmosomes strictly depends on plakophilin 1, whereas elevated levels of plakophilin 3 prevent the formation of hyperadhesive desmosomes in a protein kinase C alpha-dependent manner, even in the presence of plakophilin 1. Our study demonstrates that the balance between plakophilins 1 and 3 determines the context-dependent properties of epidermal desmosomes. In this setting, plakophilin 1 provides stable intercellular cohesion that resists mechanical stress, whereas plakophilin 3 confers dynamics as required during tissue homeostasis and repair. Our data have implications for the role of plakophilins in carcinogenesis.


Subject(s)
Calcium/metabolism , Cell Adhesion/physiology , Desmosomes/metabolism , Plakophilins/metabolism , Animals , Cell Line , Epidermal Cells , Humans , Mice , Mice, Knockout , Protein Kinase C-alpha/metabolism
10.
J Invest Dermatol ; 136(7): 1471-1478, 2016 07.
Article in English | MEDLINE | ID: mdl-27033150

ABSTRACT

Desmosomes mediate strong intercellular adhesion through desmosomal cadherins that interact with intracellular linker proteins including plakophilins (PKPs) 1-3 to anchor the intermediate filaments. PKPs show overlapping but distinct expression patterns in the epidermis. So far, the contribution of individual PKPs in differentially regulating desmosome function is incompletely understood. To resolve the role of PKP1 we ablated the PKP1 gene. Here, we report that PKP1(-/-) mice were born at the expected mendelian ratio with reduced birth weight, but they otherwise appeared normal immediately after birth. However, their condition rapidly declined, and the mice died within 24 hours, developing fragile skin with lesions in the absence of obvious mechanical trauma. This was accompanied by sparse and small desmosomes. Newborn PKP1(-/-) mice showed disturbed tight junctions with an impaired inside-out barrier, whereas the outside-in barrier was unaffected. Keratinocytes isolated from these mice showed strongly reduced intercellular cohesion, delayed tight junction formation, and reduced transepithelial resistance and reduced proliferation rates. Our study shows a nonredundant and essential role of PKP1 in desmosome and tight junction function and supports a role of PKP1 in growth control, a function that is crucial in wound healing and epidermal carcinogenesis.


Subject(s)
Desmosomes/metabolism , Epidermis/pathology , Plakophilins/physiology , Tight Junctions/metabolism , Animals , Animals, Newborn , Carcinogenesis , Cell Adhesion , Cell Proliferation , Epidermis/metabolism , Mice , Mice, Knockout , Plakophilins/genetics , Skin/metabolism , Skin/pathology , Wound Healing
11.
Cell Commun Adhes ; 21(1): 25-42, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24460199

ABSTRACT

The regulation of adhesion and growth is important for epithelial function and dysfunction. ß-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 filaments. High expression of plakophilins in desmosomes correlates with strong intercellular cohesion and is essential for tissue integrity under mechanical stress. However, like ß-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.


Subject(s)
Desmosomes/metabolism , Plakophilins/metabolism , Animals , Cell Adhesion , Humans , Neoplasms/metabolism , Neoplasms/pathology , Plakophilins/chemistry , Plakophilins/genetics , Signal Transduction , beta Catenin/metabolism , rho GTP-Binding Proteins/metabolism
12.
J Cell Sci ; 127(Pt 1): 60-71, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24163434

ABSTRACT

p0071 is an intercellular junction protein of the p120 catenin family. We have identified Rab11a as a novel interaction partner of p0071. p0071 interacted preferentially with active Rab11a. Knockdown experiments revealed an interdependent regulation of both proteins. On the one hand, p0071 depletion induced a perinuclear accumulation of Rab11, suggesting a role of p0071 in the anterograde transport of Rab11 from the pericentrosomal region to the plasma membrane but not in retrograde transport. p0071 as well as Rab11 depletion increased transferrin receptor recycling indicating that p0071-induced Rab11 mislocalization interfered with Rab11 function and shifted recycling from the slow Rab11-dependent pathway to the fast Rab4-dependent pathway. When p0071 or Rab11 depletion was combined with a Rab4 knockdown the effect was reversed. On the other hand, Rab11a depletion increased p0071 recycling to cell contacts thereby identifying p0071 as a Rab11 cargo protein. This correlated with increased intercellular adhesion. Thus, we propose that p0071 has a key role in regulating recycling through the Rab11-dependent perinuclear recycling compartment, and links the regulation of adherens junctions to recycling to allow dynamic modulation of intercellular adhesion.


Subject(s)
Adherens Junctions/metabolism , Cell Membrane/metabolism , Cell Nucleus/metabolism , Plakophilins/metabolism , rab GTP-Binding Proteins/metabolism , Cell Adhesion , Cell Line, Tumor , Endosomes/metabolism , Gene Expression Regulation , Humans , Plakophilins/antagonists & inhibitors , Plakophilins/genetics , Protein Binding , Protein Transport , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Transferrin/genetics , Receptors, Transferrin/metabolism , Signal Transduction , rab GTP-Binding Proteins/antagonists & inhibitors , rab GTP-Binding Proteins/genetics , rab4 GTP-Binding Proteins/genetics , rab4 GTP-Binding Proteins/metabolism
13.
RNA ; 19(11): 1483-96, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24062571

ABSTRACT

Loss of fragile X mental retardation protein (FMRP) causes synaptic dysfunction and intellectual disability. FMRP is an RNA-binding protein that controls the translation or turnover of a subset of mRNAs. Identifying these target transcripts is an important step toward understanding the pathology of the disease. Here, we show that FMRP regulates actin organization and neurite outgrowth via the armadillo protein p0071. In mouse embryonic fibroblasts (MEFs) lacking FMRP (Fmr1-), the actin cytoskeleton was markedly reorganized with reduced stress fibers and F-actin/G-actin ratios compared to fibroblasts re-expressing the protein. FMRP interfered with the translation of the p0071 mRNA in a 3'-UTR-dependent manner. Accordingly, FMRP-depleted cells revealed elevated levels of p0071 protein. The knockdown of p0071 in Fmr1- fibroblasts restored stress fibers and an elongated cell shape, thus rescuing the Fmr1- phenotype, whereas overexpression of p0071 in Fmr1+ cells mimicked the Fmr1- phenotype. Moreover, p0071 and FMRP regulated neurite outgrowth and branching in a diametrically opposed way in agreement with the negative regulation of p0071 by FMRP. These results identify p0071 as an important and novel FMRP target and strongly suggest that impaired actin cytoskeletal functions mediated by an excess of p0071 are key aspects underlying the fragile X syndrome.


Subject(s)
Fragile X Mental Retardation Protein/metabolism , Neurites/metabolism , Plakophilins/metabolism , Actin Cytoskeleton/metabolism , Animals , Base Sequence , Cell Line, Tumor , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Gene Expression Regulation , HEK293 Cells , Humans , Mice , Mice, Knockout , Molecular Sequence Data , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Plakophilins/genetics , RNA Interference , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism
14.
Biol Chem ; 394(8): 1005-17, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23640939

ABSTRACT

P0071 is a member of a subfamily of armadillo proteins that also comprises p120-catenin (p120ctn), δ-catenin/NPRAP, ARVCF and the more distantly related plakophilins 1-3. These proteins share a conserved central domain consisting of a series of repeated motifs, the armadillo repeats, which is flanked by more diverse amino- and carboxy-terminal domains. P0071 and the related proteins were first described as components of adherens junctions with a function in clustering and stabilizing cadherins, thereby controlling intercellular adhesion. In addition, these proteins show a cytoplasmic and a nuclear localization. Major progress in understanding their cytoplasmic role has been made in recent years. One common theme appears to be the spatiotemporal control of the small GTPases of the Rho family in various cellular contexts, such as cell adhesion and motility, cell division or neurite outgrowth. In this review article, we focus on the functions of the p0071 protein and its closest relatives in regulating cell adhesion and cytoskeletal organization, which are critically involved in the control of cell polarity. Understanding p0071's multiple functions requires assigning specific functions to particular binding partners and subcellular compartments. The identification of several new p0071 interacting proteins has promoted our understanding of the complex functions of this protein. Moreover, an initial analysis of its regulation begins to shed light on how these functions are coordinated in a cellular context.


Subject(s)
Cytoskeleton/metabolism , Plakophilins/metabolism , Protein Interaction Maps , Animals , Catenins/analysis , Catenins/metabolism , Cell Adhesion , Humans , Plakophilins/analysis , rho GTP-Binding Proteins/analysis , rho GTP-Binding Proteins/metabolism , Delta Catenin
15.
J Cell Sci ; 122(Pt 8): 1174-83, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19339549

ABSTRACT

P0071 (plakophilin-4) is a member of the p120ctn subfamily of armadillo proteins that are essential for cell contact formation. Additionally, p0071 plays a role in cytokinesis, in which it regulates local activation of RhoA together with Ect2. Because spatiotemporal regulation is required for progression through cytokinesis, we analyzed when and how p0071 is targeted to the midbody to induce RhoA activation. We show that Ect2 precedes p0071 accumulation at the midbody and that targeting is mediated by different motor proteins. p0071 interacted with the kinesin-II family member KIF3b, and knockdown of KIF3b interfered with p0071 midbody recruitment whereas Ect2 or RhoA localization was not affected in these cells. Moreover, knockdown of KIF3b induced a similar phenotype as the p0071 knockdown, with reduced actin and phospho-myosin-light-chain accumulation at the midbody and decreased levels of active RhoA during cytokinesis. The lack of RhoA activation in KIF3b-deficient cells was not rescued by overexpression of wild-type p0071 but was substantially ameliorated by a p0071-MKLP1-motor-domain fusion protein that was targeted to the furrow independently of KIF3. These data indicate that p0071 and Ect2 are transported via distinct motors and identify a novel pathway implicating KIF3 in the regulation of actin organization during cytokinesis.


Subject(s)
Cell Nucleus Division , Cytokinesis , Kinesins/metabolism , Microtubules/metabolism , Plakophilins/metabolism , Actins/metabolism , Enzyme Activation , HeLa Cells , Humans , Kinesins/genetics , Mutagenesis, Site-Directed , Mutation , Myosin Light Chains/metabolism , Phosphorylation , Plakophilins/genetics , Protein Transport , Proto-Oncogene Proteins/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Recombinant Fusion Proteins/metabolism , Transfection , rhoA GTP-Binding Protein/metabolism
16.
Cell Cycle ; 6(2): 122-7, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-17264675

ABSTRACT

P120(ctn) is the prototype of a subfamily of armadillo proteins that also comprises p0071, delta-catenin, ARVCF and the more distantly related plakophilins 1-3. These proteins have well established roles in regulating adherens junction and desmosome formation which critically depends on their capacity to cluster cadherins. Besides this function in cell adhesion that is mediated by a membrane associated pool, these proteins also show cytoplasmic and nuclear localization. While their nuclear function is still enigmatic, major progress in understanding their cytoplasmic role has been made. In the cytoplasm, the p120 catenins appear responsible for the spatio-temporal control of small Rho-GTPases in various cellular contexts. Whereas p120(ctn) has a major function in regulating cell adhesion and motility through controlling Rho-GTPases, a recent report shows that the closely related protein p0071 associates and regulates RhoA at the cleavage furrow during cytokinesis. Overexpression and knockdown of p0071 induced a cytokinesis defect that was mediated by up- or downregulation of RhoA activity at the contractile ring. There, p0071 interacted directly with RhoA itself and with the Rho-GEF Ect2. Full activation of RhoA required Ect2 as well as p0071 indicating that these two proteins act in conjunction to regulate RhoA during cytokinesis. Here we discuss the function of p120 catenins as versatile scaffolds that confer specificity to the complex regulation of Rho-GTPases. By controlling numerous stimulating guanine exchange factors (GEFs) and inhibiting GTPase activating proteins (GAPs) via the formation of multiprotein complexes at the right time and place, they direct the spatio-temporal control of Rho-signalling.


Subject(s)
Cell Adhesion Molecules/physiology , Cytokinesis/physiology , Phosphoproteins/physiology , Plakophilins/physiology , rhoA GTP-Binding Protein/metabolism , Animals , Catenins , Cell Adhesion/physiology , Cell Adhesion Molecules/chemistry , Humans , Phosphoproteins/chemistry , Plakophilins/chemistry , Signal Transduction/physiology , rhoA GTP-Binding Protein/chemistry , Delta Catenin
17.
Nat Cell Biol ; 8(12): 1432-40, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17115030

ABSTRACT

Cytokinesis requires the spatio-temporal coordination of cell-cycle control and cytoskeletal reorganization. Members of the Rho-family of GTPases are crucial regulators of this process and assembly of the contractile ring depends on local activation of Rho signalling. Here, we show that the armadillo protein p0071, unlike its relative p120(ctn), is localized at the midbody during cytokinesis and is essential for cell division. Both knockdown and overexpression of p0071 interfered with normal cell growth and survival due to cytokinesis defects with formation of multinucleated cells and induction of apoptosis. This failure of cytokinesis seemingly correlated with the deregulation of Rho activity in response to altered p0071 expression. The function of p0071 in regulating Rho activity occurred through an association of p0071 with RhoA, as well as the physical and functional interaction of p0071 with Ect2, the one Rho guanine-nucleotide exchange factor (GEF) essential for cytokinesis. These findings support an essential role for p0071 in spatially regulating restricted Rho signalling during cytokinesis.


Subject(s)
Armadillo Domain Proteins/metabolism , Cytokinesis , Plakophilins/metabolism , Signal Transduction , rhoA GTP-Binding Protein/metabolism , Animals , Centrosome/metabolism , Down-Regulation , Humans , Mice , NIH 3T3 Cells , Protein Binding , Proto-Oncogene Proteins/metabolism , RNA Interference , Spindle Apparatus/metabolism
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