Telophase correction refines division orientation in stratified epithelia

During organogenesis, precise control of spindle orientation balances proliferation and differentiation. In the developing murine epidermis, planar and perpendicular divisions yield symmetric and asymmetric fate outcomes, respectively. Classically, division axis specification involves centrosome migration and spindle rotation, events occurring early in mitosis. Here, we identify a novel orientation mechanism which corrects erroneous anaphase orientations during telophase. The directionality of reorientation correlates with the maintenance or loss of basal contact by the apical daughter. While the scaffolding protein LGN is known to determine initial spindle positioning, we show that LGN also functions during telophase to reorient oblique divisions toward perpendicular. The fidelity of telophase correction also relies on the tension-sensitive adherens junction proteins vinculin, α-E-catenin, and afadin. Failure of this corrective mechanism impacts tissue architecture, as persistent oblique divisions induce precocious, sustained differentiation. The division orientation plasticity provided by telophase correction may enable progenitors to adapt to local tissue needs.

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Telophase correction refines division orientation in stratified epithelia

10.1101/668244 ◽

2019 ◽

Author(s):

Kendall J. Lough ◽

Kevin M. Byrd ◽

Carlos P. Descovich ◽

Danielle C. Spitzer ◽

Abby J. Bergman ◽

...

Keyword(s):

Adherens Junction ◽

Scaffolding Protein ◽

Spindle Positioning ◽

Precise Control ◽

Extrinsic Cues ◽

Spindle Rotation ◽

Proliferation And Differentiation ◽

Local Cell ◽

Division Axis ◽

Adherens Junction Proteins

ABSTRACTDuring organogenesis, precise control of spindle orientation ensures a proper balance of proliferation and differentiation. In the developing murine epidermis, planar and perpendicular divisions yield symmetric and asymmetric fate outcomes, respectively. Classically, division axis specification involves centrosome migration and spindle rotation, events that occur early in mitosis. Here, we identify a previously uncharacterized orientation mechanism that occurs during telophase, correcting erroneous oblique orientations that unexpectedly persist into anaphase. The directionality of reorientation—towards either planar or perpendicular—correlates with the maintenance or loss of basal contact by the apical daughter. While the conserved scaffolding protein Pins/LGN is believed to function primarily through initial spindle positioning, we now show it also functions actively during telophase to reorient oblique divisions toward perpendicular. The ability to undergo telophase correction is also critically dependent upon an LGN-independent pathway involving the tension-sensitive adherens junction proteins vinculin, a-catenin and afadin, and correction directionality is influenced by local cell density. Failure of this reorientation mechanism impacts tissue architecture, as excessive oblique divisions induce precocious differentiation. The division orientation plasticity provided by telophase correction may provide a means for progenitors to dynamically respond to extrinsic cues provided by neighboring cells in order to adapt to local tissue needs.

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Gα12 regulates epithelial cell junctions through Src tyrosine kinases

AJP Cell Physiology ◽

10.1152/ajpcell.00548.2002 ◽

2003 ◽

Vol 285 (5) ◽

pp. C1281-C1293 ◽

Cited By ~ 42

Author(s):

Tobias N. Meyer ◽

Jennifer Hunt ◽

Catherine Schwesinger ◽

Bradley M. Denker

Keyword(s):

Epithelial Cell ◽

Tyrosine Kinase ◽

Mdck Cells ◽

Adherens Junction ◽

Paracellular Permeability ◽

Cell Junctions ◽

Scaffolding Protein ◽

Junctional Complex ◽

Adherens Junction Proteins ◽

Junction Proteins

Regulation and assembly of the epithelial cell junctional complex involve multiple signaling mechanisms, including heterotrimeric G proteins. Recently, we demonstrated that Gα12 binds to the tight junction scaffolding protein ZO-1 through the SH3 domain and that activated Gα12 increases paracellular permeability in Madin-Darby canine kidney (MDCK) cells (Meyer et al. J Biol Chem 277: 24855-24858, 2002). In the present studies, we explore the effects of Gα12 expression on tight and adherens junction proteins and examine downstream signaling pathways. By confocal microscopy, we detect disrupted tight and adherens junction proteins with increased actin stress fibers in constitutively active Gα12 (QLα12)-expressing MDCK cells. The normal distribution of ZO-1 and Na-K-ATPase was altered in QLα12-expressing MDCK cells, consistent with loss of polarity. We found that the tyrosine kinase inhibitor genistein and the Src-specific inhibitor PP-2 reversibly abrogated the QLα12 phenotype on the junctional complex. Junctional protein localization was preserved in PP-2- or genistein-treated QLα12-expressing cells, and the increase in paracellular permeability as measured by transepithelial resistance and [3H]mannitol flux was prevented by the inhibitors. Src activity was increased in QLα12-expressing MDCK cells as assessed by Src autophosphorylation, and β-catenin tyrosine phosphorylation was also increased, although there was no detectable increase in Rho activity. Taken together, these results indicate that Gα12 regulates MDCK cell junctions, in part through Src tyrosine kinase pathways.

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Drosophila p120catenin plays a supporting role in cell adhesion but is not an essential adherens junction component

The Journal of Cell Biology ◽

10.1083/jcb.200211083 ◽

2003 ◽

Vol 160 (3) ◽

pp. 433-449 ◽

Cited By ~ 94

Author(s):

Steven H. Myster ◽

Robert Cavallo ◽

Charles T. Anderson ◽

Donald T. Fox ◽

Mark Peifer

Keyword(s):

Cell Adhesion ◽

Adherens Junctions ◽

Adherens Junction ◽

Null Alleles ◽

Juxtamembrane Region ◽

Genes Encoding ◽

Positive Modulator ◽

Adherens Junction Proteins ◽

Junction Structure ◽

Junction Proteins

Cadherin–catenin complexes, localized to adherens junctions, are essential for cell–cell adhesion. One means of regulating adhesion is through the juxtamembrane domain of the cadherin cytoplasmic tail. This region is the binding site for p120, leading to the hypothesis that p120 is a key regulator of cell adhesion. p120 has also been suggested to regulate the GTPase Rho and to regulate transcription via its binding partner Kaiso. To test these hypothesized functions, we turned to Drosophila, which has only a single p120 family member. It localizes to adherens junctions and binds the juxtamembrane region of DE-cadherin (DE-cad). We generated null alleles of p120 and found that mutants are viable and fertile and have no substantial changes in junction structure or function. However, p120 mutations strongly enhance mutations in the genes encoding DE-cadherin or Armadillo, the β-catenin homologue. Finally, we examined the localization of p120 during embryogenesis. p120 localizes to adherens junctions, but its localization there is less universal than that of core adherens junction proteins. Together, these data suggest that p120 is an important positive modulator of adhesion but that it is not an essential core component of adherens junctions.

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Ectopic expression of gastrokine 1 in gastric cancer cells up-regulates tight and adherens junction proteins network

Pathology - Research and Practice ◽

10.1016/j.prp.2015.04.008 ◽

2015 ◽

Vol 211 (8) ◽

pp. 577-583 ◽

Cited By ~ 10

Author(s):

Emilia Rippa ◽

Filomena Altieri ◽

Chiara Stella Di Stadio ◽

Giuseppina Miselli ◽

Annalisa Lamberti ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Ectopic Expression ◽

Adherens Junction ◽

Gastric Cancer Cells ◽

Gastrokine 1 ◽

Adherens Junction Proteins ◽

Junction Proteins

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Altered expression and interaction of adherens junction proteins in the developing OLM of the Rho(−/−) mouse

Experimental Eye Research ◽

10.1016/j.exer.2007.08.004 ◽

2007 ◽

Vol 85 (5) ◽

pp. 714-720 ◽

Cited By ~ 12

Author(s):

Matthew Campbell ◽

Marian Humphries ◽

Paul Kenna ◽

Peter Humphries ◽

Brenda Brankin

Keyword(s):

Adherens Junction ◽

Altered Expression ◽

Adherens Junction Proteins ◽

Junction Proteins

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Regulation of Adherens Junction Dynamics by Phosphorylation Switches

Journal of Signal Transduction ◽

10.1155/2012/125295 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 26

Author(s):

Cristina Bertocchi ◽

Megha Vaman Rao ◽

Ronen Zaidel-Bar

Keyword(s):

Actin Cytoskeleton ◽

Enzymatic Activity ◽

Adherens Junctions ◽

Adherens Junction ◽

Adaptor Proteins ◽

Cell Junction ◽

Internal Forces ◽

Adherens Junction Proteins ◽

Junction Proteins

Adherens junctions connect the actin cytoskeleton of neighboring cells through transmembrane cadherin receptors and a network of adaptor proteins. The interactions between these adaptors and cadherin as well as the activity of actin regulators localized to adherens junctions are tightly controlled to facilitate cell junction assembly or disassembly in response to changes in external or internal forces and/or signaling. Phosphorylation of tyrosine, serine, or threonine residues acts as a switch on the majority of adherens junction proteins, turning “on” or “off” their interactions with other proteins and/or their enzymatic activity. Here, we provide an overview of the kinases and phosphatases regulating phosphorylation of adherens junction proteins and bring examples of phosphorylation events leading to the assembly or disassembly of adherens junctions, highlighting the important role of phosphorylation switches in regulating their dynamics.

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