Abl tyrosine kinases modulate cadherin-dependent adhesion upstream and downstream of Rho family GTPases

Zandy, Nicole Lynn; Pendergast, Ann Marie

doi:10.4161/cc.7.4.5452

Cited by 52 publications

(57 citation statements)

References 35 publications

(60 reference statements)

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“…The diminished PDGFR and IGF-IR activity leads to reduction in activity of c-Abl kinase, as well as activity of downstream effectors that are known to modulate Ecadherin function (48). Nearly all these factors have been reported to regulate E-cadherin function (35,42,48); however, their control by Cdx2 is novel, as is their placement by us within the context of colon cancer cell-cell adhesion.…”

Section: Discussionmentioning

confidence: 99%

“…Nearly all these factors have been reported to regulate E-cadherin function (35,42,48); however, their control by Cdx2 is novel, as is their placement by us within the context of colon cancer cell-cell adhesion. Additionally, this finding resolves a long-standing unresolved question regarding Cdx2's tumor-suppressor qualities.…”

Section: Discussionmentioning

confidence: 99%

“…This treatment also reduced the level of CrkL phosphorylation. CrkL is an adaptor protein that is activated by Abl kinase phosphorylation and is an important effector for c-Abl kinase activity (42,48).…”

Section: Reduction In C-abl Kinase Activation By Cdx2 Promotes Cell-cmentioning

confidence: 99%

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Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Funakoshi

Kong

Crissey

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane. Am J Physiol Gastrointest Liver Physiol 299: G1054 -G1067, 2010. First published July 29, 2010; doi:10.1152/ajpgi.00297.2010.-Cdx2 is an intestine-specific transcription factor required for normal intestinal epithelium development. Cdx2 regulates the expression of intestine-specific genes and induces cell adhesion and columnar morphogenesis. Cdx2 also has tumor-suppressor properties, including the reduction of colon cancer cell proliferation and cell invasion, the latter due to its effects on cell adhesion. E-cadherin is a cell adhesion protein required for adherens junction formation and the establishment of intestinal cell polarity. The objective of this study was to elucidate the mechanism by which Cdx2 regulates E-cadherin function. Two colon cancer cell lines were identified in which Cdx2 expression was associated with increased cell-cell adhesion and diminished cell migration. In both cell lines, Cdx2 did not directly alter E-cadherin levels but increased its trafficking to the cell membrane compartment. Cdx2 enhanced this trafficking by altering receptor tyrosine kinase (RTK) activity. Cdx2 expression diminished phosphorylated Abl and phosphorylated Rac levels, which are downstream effectors of RTKs. Specific chemical inhibition or short interfering RNA (shRNA) knockdown of c-Abl kinase phenocopied Cdx2's cell-cell adhesion effects. In Colo 205 cells, Cdx2 reduced PDGF receptor and IGF-I receptor activation. This was mediated by caveolin-1, which was induced by Cdx2. Targeted shRNA knockdown of caveolin-1 restored PDGF receptor and reversed E-cadherin membrane trafficking, despite Cdx2 expression. We conclude that Cdx2 regulates E-cadherin function indirectly by disrupting RTK activity and enhancing E-cadherin trafficking to the cell membrane compartment. This novel mechanism advances Cdx2's prodifferentiation and antitumor properties and suggests that Cdx2 may broadly regulate RTK activity in normal intestinal epithelium by modulating membrane trafficking of proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Funakoshi

Kong

Crissey

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The final curve is projected onto the adjacent time points after adjusting its position using the optical flow (Raffel et al, 1998), and the process is iterated. We demonstrate the use of MEDUSA by identifying a wound-closure phenotype in mutants for Abl, which regulates actin organization and junctional dynamics (Zandy and Pendergast, 2008).…”

Section: Discussionmentioning

confidence: 99%

Automated multidimensional image analysis reveals a role for Abl in embryonic wound repair

et al. 2014

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The embryonic epidermis displays a remarkable ability to repair wounds rapidly. Embryonic wound repair is driven by the evolutionary conserved redistribution of cytoskeletal and junctional proteins around the wound. Drosophila has emerged as a model to screen for factors implicated in wound closure. However, genetic screens have been limited by the use of manual analysis methods. We introduce MEDUSA, a novel image-analysis tool for the automated quantification of multicellular and molecular dynamics from timelapse confocal microscopy data. We validate MEDUSA by quantifying wound closure in Drosophila embryos, and we show that the results of our automated analysis are comparable to analysis by manual delineation and tracking of the wounds, while significantly reducing the processing time. We demonstrate that MEDUSA can also be applied to the investigation of cellular behaviors in three and four dimensions. Using MEDUSA, we find that the conserved nonreceptor tyrosine kinase Abelson (Abl) contributes to rapid embryonic wound closure. We demonstrate that Abl plays a role in the organization of filamentous actin and the redistribution of the junctional protein β-catenin at the wound margin during embryonic wound repair. Finally, we discuss different models for the role of Abl in the regulation of actin architecture and adhesion dynamics at the wound margin.

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“…Interestingly, genetic loss, knockdown or pharmacological inhibition of both Abl and Arg leads to disruption of N-cadherinand E-cadherin-based cell-cell contacts (Zandy and Pendergast, 2008;Zandy et al, 2007). Conversely, cell-cell adhesion enhances Abl-family kinase activity through an as-yet-unknown mechanism, which leads to increased CrkII phosphorylation and subsequent Rac activation (Abassi and Vuori, 2002;Burton et al, 2005).…”

Section: Regulation Of Cell-cell Adhesionmentioning

confidence: 99%

Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts

Bradley

Koleske

2009

Journal of Cell Science

158

206

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The Abl-family non-receptor tyrosine kinases are essential regulators of the cytoskeleton. They transduce diverse extracellular cues into cytoskeletal rearrangements that have dramatic effects on cell motility and morphogenesis. Recent biochemical and genetic studies have revealed several mechanisms that Abl-family kinases use to mediate these effects. Abl-family kinases stimulate actin polymerization through the activation of cortactin, hematopoietic lineage cell-specific protein (HS1), WASp-and WAVE-family proteins, and Rac1. They also attenuate cell contractility by inhibiting RhoA and altering adhesion dynamics. These pathways impinge on several physiological processes, including development and maintenance of the nervous and immune systems, and epithelial morphogenesis. Elucidating how Abl-family kinases are regulated, and where and when they coordinate cytoskeletal changes, is essential for garnering a better understanding of these complex processes.

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Abl tyrosine kinases modulate cadherin-dependent adhesion upstream and downstream of Rho family GTPases

Cited by 52 publications

References 35 publications

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Automated multidimensional image analysis reveals a role for Abl in embryonic wound repair

Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts

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