The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl–Crk pathway

Noren, Nicole K.; Foos, Gabriele; Hauser, Craig A.; Pasquale, Elena B.

doi:10.1038/ncb1438

Cited by 268 publications

(315 citation statements)

References 49 publications

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“…Previous studies also demonstrated that activation of EphB receptors by ephrin-B1 or ephrin-B2 results in the activation of E-cadherin adhesion (41,42). These studies are consistent with our observations here that the loss of ephrin-A5 leads to the disruption of N-cadherin-␤-catenin interactions, resulting in a loss of cell-cell adhesion.…”

Section: Regulation Of N-cadherin and ␤-Cateninsupporting

confidence: 82%

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Cooper

Son

Komlos³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

125

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Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of ephrin-A5 KO mice. We further demonstrate that ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of ␤-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.␤-catenin ͉ Eph receptor ͉ N-cadherin C ataract, or the opacification of the lens, is the leading cause of visual impairment and blindness worldwide (1). The molecular events underlying lens development and the processes by which the lens maintains transparency over a lifetime are unclear (2). In addition, the cellular and biochemical mechanisms underlying the pathological changes leading to cataract remain poorly understood.The lens is composed of a single layer of epithelial cells on the anterior surface, which, over a lifetime, divide and differentiate into the underlying lens fiber cells that comprise the bulk of the lens (3, 4). Initially during lens development, primary lens fiber cells differentiate and elongate from the posterior pole. In later embryogenesis and throughout life, secondary lens fiber cells differentiate from lens epithelial cells located at the equator. In cross section, the lens fiber cells resemble flattened hexagons with two broad and four short sides (3). These cells are organized in a highly ordered and closely packed manner, and interact through extensive intercellular adhesion complexes including gap and adherens junctions (5). Fiber cell gap junctions are composed of connexins (Cx) 46 and 50 (6), inactivation of which leads to the degeneration of the inner fiber cells and the development of cataract in mice (7,8). Mutations in human Cx genes have also been associated with cataractogenesis (9, 10). As the lens is completely enclosed by an acellular, avascular capsule, it is believed that these cell-cell junctions are critical for providing nutrient transport, removal of metabolic wastes, and maintenance of homeostasis (11,12). In addition to gap junctions, widespread adherens junctions containing N-cadherin and its associated protein ␤-catenin exist between lens fiber cells (13-16), and may play important roles in lens development and function.Although cell-cell interaction is critical for maintaining lens transparency, little is known about the molecular mechanisms underlying these interactions. We have identified an unexpected regulator of lens fiber cell-cell interaction, the axon guidance molecule ephrin-A5 (17)(18)(19), and have shown that the loss...

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Section: Regulation Of N-cadherin and ␤-Cateninsupporting

confidence: 82%

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Cooper

Son

Komlos³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

125

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“…Although the mechanism by which BCR-Abl drives leukemiagenesis is well understood, there is little information on the effects of Abl proteins on the development or progression of solid tumors (Singer et al, 2004;Van Diest et al, 2004;Nahta et al, 2005;Nagano et al, 2006;Noren et al, 2006;Vantaggiato et al, 2006). Here, we identify a novel mechanism by which c-Abl promotes breast cancer cell growth and invasion by upregulating ERa expression (Figure 6).…”

Section: Discussionmentioning

confidence: 88%

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

He¹,

Zheng²,

Song³

et al. 2010

Oncogene

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Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligandactivated transcription factors. Similar to other steroid hormone receptors, estrogen receptor a (ERa) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERa associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERa and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERa can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERa phosphorylation by c-Abl stabilizes ERa, resulting in enhanced ERa transcriptional activity and increased expression of endogenous ERa target genes. Furthermore, ERa phosphorylation at the Y-219 site affects DNA binding and dimerization by ERa. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Ablinduced accumulation of ERa and enhancement of ERa transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERa function. Moreover, the ERa (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERa expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.

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“…More recently, ephrin/Eph cues have been shown to be pro-apoptotic in other cellular contexts (Figueroa et al 2006;Noren et al 2006), but also in some cases they seem to act as prosurvival factors, at least in adult mouse neural stem cells (Furne et al 2009;Ricard et al 2006). In the latter case, it has been proposed that EphA4 may act as a dependence receptor that would promote cell death in the absence of ephrin ligands, following caspase cleavage processes similar to the ones described for DCC and Unc5 (Furne et al 2009).…”

Section: Ephrinsmentioning

confidence: 99%

Guidance Molecules in Axon Pruning and Cell Death

Vanderhaeghen¹,

Cheng²

2010

Cold Spring Harbor Perspectives in Biology

114

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Axon pruning and neuronal cell death constitute two major regressive events that enable the establishment of fully mature brain architecture and connectivity. Although the cellular mechanisms for these two events are thought to be distinct, recent evidence has indicated the direct involvement of axon guidance molecules, including semaphorins, netrins, and ephrins, in controlling both processes. Here, we review how axon guidance cues regulate regressive events in paradigmatic models of neural development, from early control of apoptosis of neural progenitors, to later maintenance of neuronal survival and stereotyped pruning of axonal branches. These new findings are also discussed in the context of neural diseases and the potential links between axon pruning and degeneration. REGRESSIVE EVENTS IN NEURONAL DEVELOPMENT

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The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl–Crk pathway

Cited by 268 publications

References 49 publications

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

Guidance Molecules in Axon Pruning and Cell Death

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