Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell–cell adhesion

Calautti, Enzo; Grossi, Maddalena; Mammucari, Cristina; Aoyama, Yumi; Pirro, Maria Teresa; Ono, Yoshitaka; Li, Jie; Dotto, G. Paolo

doi:10.1083/jcb.200105140

Cited by 156 publications

(163 citation statements)

References 45 publications

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“…39,40,[44][45][46][47] Our study identifies CDK10/CycM as a key upstream regulator of this biology. Combining our and previous observations, we propose a model in which CDK10/ CycM phosphorylates PKN2 within its RhoA binding domain, thereby promoting RhoA binding and stabilization, which results in actin polymerization and consequent repression of primary cilia formation at cell cycle exit (Fig.…”

Section: Discussionmentioning

confidence: 78%

“…This model is intriguing given the location of the CDK10/CycM phophosphorylation sites within PKN2, and the fact that cell-cell adhesion regulation depends upon the ability of PKN2 to bind RhoA, and vice versa. 44,45 If this model is correct, based on prior studies, 39 it must require active PKN2 kinase. In the second mechanism, CDK10/CycM-PKN2 could actively inhibit the Smurf1 complex.…”

Section: Discussionmentioning

confidence: 99%

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STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

et al. 2016

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CDK10/CycM is a protein kinase deficient in STAR (toe Syndactyly, Telecanthus and Anogenital and Renal malformations) syndrome, which results from mutations in the X-linked FAM58A gene encoding Cyclin M. The biological functions of CDK10/CycM and etiology of STAR syndrome are poorly understood. Here, we report that deficiency of CDK10/Cyclin M promotes assembly and elongation of primary cilia. We establish that this reflects a key role for CDK10/Cyclin M in regulation of actin network organization, which is known to govern ciliogenesis. In an unbiased screen, we identified the RhoA-associated kinase PKN2 as a CDK10/ CycM phosphorylation substrate. We establish that PKN2 is a bone fide regulator of ciliogenesis, acting in a similar manner to CDK10/CycM. We discovered that CDK10/Cyclin M binds and phosphorylates PKN2 on threonines 121 and 124, within PKN2 0 s core RhoA-binding domain. Furthermore, we demonstrate that deficiencies in CDK10/CycM or PKN2, or expression of a non-phosphorylatable version of PKN2, destabilize both the RhoA protein and the actin network architecture. Importantly, we established that ectopic expression of RhoA is sufficient to override the induction of ciliogenesis resulting from CDK10/CycM knockdown, indicating that RhoA regulation is critical for CDK10/CycM's negative effect on ciliogenesis. Finally, we show that kidney sections from a STAR patient display dilated renal tubules and abnormal, elongated cilia. Altogether, these results reveal CDK10/CycM as a key regulator of actin dynamics and a suppressor of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling. Moreover, they suggest that STAR syndrome is a ciliopathy.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

et al. 2016

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“…For other cadherins, it has been reported that RhoA is stimulated by N-cadherin engagement in C2C12 myoblasts (Charrasse et al, 2002) and by E-cadherin engagement in keratinocytes (Calautti et al, 2002). However, other investigators have found that cell-cell contact through cadherins inhibits RhoA activity (Noren et al, 2001;Lampugnani et al, 2002), whereas still others detect no changes in RhoA upon cadherin engagement (Nakagawa et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Nelson

Pirone

Tan

et al. 2004

MBoC

166

137

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Changes in vascular endothelial (VE)-cadherin-mediated cell-cell adhesion and integrin-mediated cell-matrix adhesion coordinate to affect the physical and mechanical rearrangements of the endothelium, although the mechanisms for such cross talk remain undefined. Herein, we describe the regulation of focal adhesion formation and cytoskeletal tension by intercellular VE-cadherin engagement, and the molecular mechanism by which this occurs. Increasing the density of endothelial cells to increase cell-cell contact decreased focal adhesions by decreasing cell spreading. This contact inhibition of cell spreading was blocked by disrupting VE-cadherin engagement with an adenovirus encoding dominant negative VE-cadherin. When changes in cell spreading were prevented by culturing cells on a micropatterned substrate, VE-cadherin-mediated cell-cell contact paradoxically increased focal adhesion formation. We show that VE-cadherin engagement mediates each of these effects by inducing both a transient and sustained activation of RhoA. Both the increase and decrease in cell-matrix adhesion were blocked by disrupting intracellular tension and signaling through the Rho-ROCK pathway. In all, these findings demonstrate that VE-cadherin signals through RhoA and the actin cytoskeleton to cross talk with cell-matrix adhesion and thereby define a novel pathway by which cell-cell contact alters the global mechanical and functional state of cells. INTRODUCTIONCoordinated changes between cell adhesion to the extracellular matrix (ECM) and to neighboring cells are crucial for the many physical transformations that cells must undergo during development, tissue homeostasis, and wound healing. In the endothelium, where a single layer of cells separates tissues from their blood supply, the concerted regulation of cell-cell and cell-ECM adhesion drives rapid changes in cell shape and vascular architecture essential to vascular remodeling in both normal and disease processes (Vestweber, 2000;Dudek and Garcia, 2001). Dynamic changes in cell-cell and cell-matrix adhesion and mechanical forces are responsible for regulating vascular permeability, and agents that alter permeability invariably affect both types of adhesion complexes (Dudek and Garcia, 2001). During blood vessel sprouting and migration in angiogenesis, endothelial cells must disassemble and reform their cell-cell and cell-ECM contacts in synchrony to generate appropriate structures. These two adhesion systems each regulate their functional effects through both biochemical and mechanical signals.Changes in integrin binding to ECM not only alter signals that regulate cell proliferation, migration, and survival (Assoian and Schwartz, 2001;Hood and Cheresh, 2002;Stupack and Cheresh, 2002) but also modulate cell mechanics by affecting focal adhesion (FA) maturation, adhesion strength, cytoskeletal contractility, and cell shape (Geiger and Bershadsky, 2002;Juliano, 2002). Likewise, changes in the engagement of vascular endothelial (VE)-cadherin, the principal junctional molecule in endothe...

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“…Cell aggregation assays, which allow overall estimation of desmosome formation before they become calcium-insensitive, were performed essentially as described previously 51 Immunofluorescence staining of mouse skin. Frozen sections of mouse tail skin (7 mm) were incubated with antibodies against mouse Dsc2 (R&D Systems, Minneapolis, MN) or desmoplakin 52 together with Hoechst to counterstain nuclei.…”

Section: Methodsmentioning

confidence: 99%

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

et al. 2014

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The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.

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Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell–cell adhesion

Cited by 156 publications

References 45 publications

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

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