Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling

Ashton, G H S; Morton, Jennifer P.; Myant, Kevin; Phesse, Toby J.; Ridgway, Rachel A.; Marsh, Victoria; Wilkins, Julie; Athineos, Dimitris; Muncan, Vanesa; Kemp, Richard; Neufeld, Kristi L.; Clevers, Hans; Brunton, Valerie G.; Winton, Douglas J.; Wang, Xiaoyan; Sears, Rosalie C.; Clarke, Alan R.; Frame, Margaret C.; Sansom, Owen J.

doi:10.1016/j.devcel.2010.07.015

Cited by 179 publications

(207 citation statements)

References 53 publications

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“…Consistent with this idea, Ret expression leads to both Src42A and Fak phosphorylation, but we find that the two kinases have opposing effects on proliferation: Src42A promotes proliferation downstream of Ret, whereas Fak blocks it. Hence, despite the fact that blocking Fak function may represent a therapeutic opportunity in some cancers (Ashton et al , 2010; Lee et al , 2015), our findings are more aligned with a previous study (Macagno et al , 2014) that suggested that, at least in the context of Ret‐driven tumorigenesis, Fak can act as a tumour suppressor. In future, it will also be of interest to explore how the Ras/Raf/Erk pathway, activated by Ret in other contexts and previously shown to affect ISC proliferation in flies (Buchon et al , 2010; Biteau & Jasper, 2011; Jiang et al , 2011), intersects with Src/Fak/Wg signalling in response to Ret activation.…”

Section: Discussionsupporting

confidence: 87%

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

et al. 2017

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Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homeostatic contexts. They also suggest an epithelial contribution to Ret loss‐of‐function disorders such as Hirschsprung disease.

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Section: Discussionsupporting

confidence: 87%

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

et al. 2017

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“…Indeed, intestinal stem cells that escaped from massive p53-mediated apoptosis undergo cell proliferation and repopulate the intestine within a few days, a process that critically relies on Wnt signaling (Withers and Elkind, 1970;Merritt et al, 1994;Ashton et al, 2010;Cordero and Sansom, 2012). The mitotically active Lgr5 + cells, although dispensable for intestinal homeostasis, are critical for intestinal regeneration upon damage.…”

Section: Elp3 Drives Wnt-dependent Tumor Initiation and Regeneration mentioning

confidence: 99%

Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Ladang¹,

Rapino²,

Heukamp³

et al. 2015

J Cell Biol

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“…However, the effect of Ctnnb1 activation on loss of differentiation markers and cell adhesiveness was much greater. Similar to other cell types, the Wnt/Ctnnb1 pathway in podocytes appears to interact with integrin and focal adhesion kinase signaling pathways (41). The overall effect of Wnt/Ctnnb1 activation was podocyte detachment and the development of albuminuria.…”

Section: Discussionmentioning

confidence: 97%

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Kato

Gruenwald

Suh

et al. 2011

Journal of Biological Chemistry

176

193

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Diabetic kidney disease (DKD) is the single most common cause of albuminuria and end-stage kidney disease in the UnitedStates. We found increased expression of Wnt/␤-catenin (Ctnnb1) pathway transcripts and proteins in glomeruli and podocytes of patients and mouse models of DKD. Mice with podocyte-specific expression of stabilized Ctnnb1 exhibited basement membrane abnormalities, albuminuria, and increased susceptibility to glomerular injury. Mice with podocyte-specific deletion of Ctnnb1 or podocyte-specific expression of the canonical Wnt inhibitor Dickkopf-related protein 1 (Dkk1) also showed increased susceptibility to DKD. Podocytes with stabilized Ctnnb1 were less motile and less adhesive to different matrices. Deletion of Ctnnb1 in cultured podocytes increased the expression of podocyte differentiation markers and enhanced cell motility; however, these cells were more susceptible to apoptosis. These results indicate that Wnt/Ctnnb1 signaling in podocytes plays a critical role in integrating cell adhesion, motility, cell death, and differentiation. Balanced Ctnnb1 expression is critical for glomerular filtration barrier maintenance. Diabetic kidney disease (DKD)2 is one of the most devastating complications of diabetes and the single most common cause of albuminuria, chronic kidney disease, and end-stage renal disease (ESRD) in the Western world (1). DKD causes filtration unit dysfunction leading to the development of albuminuria, which is the most abundant protein component of the blood. The glomerular filtration barrier consists of three layers as follows: glomerular endothelial cells, the glomerular basement membrane (GBM), and the glomerular epithelial cell (or podocyte) layer (2-4). Decreased glomerular podocyte density is shown to be the strongest predictor for end-stage renal disease development in patients with diabetes (5). Hyperglycemia via the generation of reactive oxygen species induces podocyte apoptosis and loss, which has been well documented in many different mouse DKD models (6, 7). As podocytes are terminally differentiated cells, they are unable to proliferate; therefore, apoptosis or detachment can lead to podocyte deficiency, which in turn will lead to glomerulosclerosis development (8, 9). Early administration of drugs that prevent podocyte apoptosis has been shown to ameliorate DKD in rodent models; however, this may not be a clinically translatable strategy (6, 10). Another early lesion in diabetes is the thickening of the basement membrane. The role and mechanism of GBM thickening are not fully understood. It is speculated that GBM thickening could cause alterations in integrin expression, which could interfere with podocyte adhesiveness. Genetic deletion of podocyte-specific integrins, Itgb1 and Itga3, causes albuminuria and glomerulosclerosis; however, the contribution of podocyte adhesion to DKD development has not been demonstrated (11,12). Understanding the mechanism of podocyte differentiation, adhesion and cell death could be highly relevant for the development of targets f...

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Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling

Cited by 179 publications

References 53 publications

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

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