Drosophila Abelson kinase mediates cell invasion and proliferation through two distinct MAPK pathways

Singh, Jaskirat; Aaronson, Stuart A.; Mlodzik, Marek

doi:10.1038/onc.2010.155

Cited by 27 publications

(26 citation statements)

References 46 publications

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“…Abl is known to affect adhesion levels in multiple tissues [26], [48], [52], [53], usually by destabilizing adherens junctions. Therefore, we focused on cadherins, rather than integrins as a potential mechanism for adhesion-based stem cell competition in Abl mutant CySCs.…”

Section: Resultsmentioning

confidence: 99%

Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

et al. 2014

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Stem cells in tissues reside in and receive signals from local microenvironments called niches. Understanding how multiple signals within niches integrate to control stem cell function is challenging. The Drosophila testis stem cell niche consists of somatic hub cells that maintain both germline stem cells and somatic cyst stem cells (CySCs). Here, we show a role for the axon guidance pathway Slit-Roundabout (Robo) in the testis niche. The ligand Slit is expressed specifically in hub cells while its receptor, Roundabout 2 (Robo2), is required in CySCs in order for them to compete for occupancy in the niche. CySCs also require the Slit-Robo effector Abelson tyrosine kinase (Abl) to prevent over-adhesion of CySCs to the niche, and CySCs mutant for Abl outcompete wild type CySCs for niche occupancy. Both Robo2 and Abl phenotypes can be rescued through modulation of adherens junction components, suggesting that the two work together to balance CySC adhesion levels. Interestingly, expression of Robo2 requires JAK-STAT signaling, an important maintenance pathway for both germline and cyst stem cells in the testis. Our work indicates that Slit-Robo signaling affects stem cell function downstream of the JAK-STAT pathway by controlling the ability of stem cells to compete for occupancy in their niche.

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Section: Resultsmentioning

confidence: 99%

Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

et al. 2014

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“…Thus, we next investigated whether ectopic Vha44 expression activates oncogenic signaling pathways previously reported to mediate cell invasion and overgrowth in the wing disc (Vidal et al, 2006; Singh et al, 2010). Silencing the Src inhibitor Csk with a previously validated RNAi line did not significantly increase the level of Vha44-induced migration (Vidal et al, 2006; supplementary material Fig.…”

Section: Resultsmentioning

confidence: 99%

Elevated expression of the V-ATPase C subunit triggers JNK-dependent cell invasion and overgrowth in a Drosophila epithelium

Petzoldt

Gleixner

Fumagalli

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYThe C subunit of the vacuolar H+-ATPase or V-ATPase regulates the activity and assembly of the proton pump at cellular membranes. It has been shown to be strongly upregulated in oral squamous cell carcinoma, a highly metastatic epithelial cancer. In addition, increased V-ATPase activity appears to correlate with invasiveness of cancer cells, but the underlying mechanism is largely unknown. Using the Drosophila wing imaginal epithelium as an in vivo model system, we demonstrate that overexpression of Vha44, the Drosophila orthologue of the C subunit, causes a tumor-like tissue transformation in cells of the wing epithelium. Overexpressing cells are excluded from the epithelium and acquire invasive properties while displaying high apoptotic rates. Blocking apoptosis in these cells unmasks a strong proliferation stimulus, leading to overgrowth. Furthermore, we show that excess Vha44 greatly increases acidification of endocytic compartments and interferes with endosomal trafficking. As a result, cargoes such as GFP-Lamp1 and Notch accumulate in highly acidified enlarged endolysosomal compartments. Consistent with previous reports on the endocytic activation of Eiger/JNK signaling, we find that V-ATPase stimulation by Vha44 causes JNK signaling activation whereas downmodulation of JNK signaling rescues the invasive phenotypes. In summary, our in vivo-findings demonstrate that increased levels of V-ATPase C subunit induce a Eiger/JNK-dependent cell transformation within an epithelial organ that recapitulates early carcinoma stages.

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“…Drosophila Abl (D-Abl) also regulates planar cell polarity during axis elongation by modulating the tyrosine phosphorylation and localization dynamics of β-catenin 109 . Recently, D-Abl was shown to be required for planar cell polarity in the Drosophila eye and wing by regulation of Frizzled/Dishevelled signaling 110 . Furthermore, expression of activated ABL2, and to a lesser extent ABL1, induces a striking inversion of apical-basal polarity in epithelial cells grown in a 3D cell culture system in the presence of collagen 111 ( Fig.…”

Section: Abl Family Kinases Regulate Morphogenesismentioning

confidence: 99%

Role of ABL family kinases in cancer: from leukaemia to solid tumours

et al. 2013

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The Abelson (ABL) family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration, and invasion. ABL1 was first identified as an oncogene required for the development of leukemias initiated by retroviruses or chromosome translocations. The demonstration that small molecule ABL kinase inhibitors effectively treat chronic myeloid leukemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumors. Enhanced ABL expression and activation in some solid tumors, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may have utility in treating selected solid tumors.

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Drosophila Abelson kinase mediates cell invasion and proliferation through two distinct MAPK pathways

Cited by 27 publications

References 46 publications

Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

Elevated expression of the V-ATPase C subunit triggers JNK-dependent cell invasion and overgrowth in a Drosophila epithelium

Role of ABL family kinases in cancer: from leukaemia to solid tumours

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