Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor– and Vascular Endothelial Growth Factor–induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis

Yan, Wei; Bentley, Brooke; Shao, Rong

doi:10.1091/mbc.e07-10-1068

Cited by 42 publications

(43 citation statements)

References 45 publications

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“…47 This is different from our findings, in which endogenous c-Abl mediated a proapoptotic effect on endothelial cells, and its inhibition protected the endothelial cells from apoptosis. The difference may be related to our reliance on endogenous c-Abl and the use of native untransfected endothelial cells without induced immortalization, or differences in the stimuli used: bFGF in the investigation by Yan et al 47 compared with inhibition of integrin ligation and F-actin dynamics in our work. Both differences may be related to the intracellular localization of Abl in the different scenarios and its nuclear-cytosolic shuttling, where preferential cytosolic localization would be associated with bFGF-induced increased proliferation, but nuclear localization would favor apoptosis.…”

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…47 This was reversed in cells overexpressing the K290R kinase-dead c-Abl, suggesting that c-Abl mediates the proangiogenic effects of bFGF on endothelial cells. 47 This is different from our findings, in which endogenous c-Abl mediated a proapoptotic effect on endothelial cells, and its inhibition protected the endothelial cells from apoptosis. The difference may be related to our reliance on endogenous c-Abl and the use of native untransfected endothelial cells without induced immortalization, or differences in the stimuli used: bFGF in the investigation by Yan et al 47 compared with inhibition of integrin ligation and F-actin dynamics in our work.…”

Section: Discussionmentioning

confidence: 99%

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c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 and by disruption of actin

Xu¹,

Millard²,

Ren³

et al. 2010

Blood

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Inhibition of integrins IntroductionAngiogenesis and endothelial cell responses are essential processes in diseases, such as cancer, and ischemic conditions. Integrins, heterodimeric cell-surface receptors composed of ␣ and ␤ subunits, are central regulators of angiogenesis and endothelial cell functions. 1 Integrins enable cells to adhere to extracellular matrix (ECM), migrate over ECM substrates, and respond to ECM contact by proliferation, differentiation, and protection from apoptosis mediated by regulation of a number of intracellular signaling pathways. 1-3 Inhibition of integrins ␣v␤3 and ␣v␤5, which are preferentially expressed and activated on angiogenic endothelial cells, induces endothelial apoptosis and impairs tumor angiogenesis. 4,5 ␣v␤3/␣v␤5-integrin signaling is mediated through interactions with an arginine-glycine-aspartic acid (RGD) peptide sequence in matrix proteins, such as vitronectin (VN), and can be abrogated by soluble function-blocking RGD peptides, such as cyclic RGDfV. 4 Indeed, inhibitors of integrin ␣v␤3 are undergoing clinical trials in cancer patients, and cilengitide (EMD 121974; Merck KGaA), an integrin ␣v␤3/␣v␤5 function-blocking RGDfV peptide, has encouraging activity in phase 1 and 2 trials against brain tumors in children and adult cancer patients. 6,7 Integrin ␣v␤3 mechanism of action is complex. ␣v␤3 participates in pathologic angiogenesis, 4,8 supporting its development as a target for therapy. To mediate its function, integrin ␣v␤3 requires activation and phosphorylation of the ␤3 integrin tail on Tyr747 and Tyr459, which signal downstream to pathways involving, among others, Src, FAK, Shc, p53, and p21 WAF . 8,9 Complicating matters, integrin ␣v␤3 cosignals with growth factor receptors, such as vascular endothelial growth factor receptor-2 and others. 8 The intracellular signaling events mediating outside-in and inside-out signaling are complex and depend on the context of activation of the integrin and the cell type studied. Therefore, it is not surprising that the precise molecular mechanisms induced by engagement, crosstalk, or inhibition of ␣v␤3 integrin remain only partially understood.Engagement of integrins with the ECM allows cells to adhere and spread, inducing changes in the actin cytoskeleton. Actin is an abundant cytoskeletal protein important in cell spreading and motility. 10,11 Engagement of integrins with the ECM generates complex bidirectional signaling cascades between integrins and the actin cytoskeleton, which serve to transmit both force and biochemical signals. The interaction of integrins with actin is mostly through a number of intermediary proteins that can be cell-specific and/or stimulus-specific. 11 A critical molecule that interacts with F-actin in fibroblasts is c-Abl. c-Abl integrates multiple signals to coordinate F-actin dynamics, whereas F-actin itself has an inhibitory effect on c-Abl kinase activity. 12-14 Therefore, it is anticipated that actindependent signaling, including that by c-Abl, may mediate at least some of the phenotypes ...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 and by disruption of actin

Xu¹,

Millard²,

Ren³

et al. 2010

Blood

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“…31,32 In nontransformed fibroblasts, c-Abl and Arg are transiently activated downstream of receptor tyrosine kinases (RTKs), PDGFR, and EGFR 22,[33][34][35] and are activated by bFGFR in endothelial cells. 36 c-Abl also is activated by transforming growth factor-β (TGF-β) 37,38 and AT-1 (angiotensin subtype 1) receptors. 39 PDGFR stimulates c-Abl/ Arg activation via Src family kinases (SFKs), which directly phosphorylate c-Abl/Arg on Y245 and Y412, activating the kinases, 22,33 and via activation of PLC-γ, which hydrolyzes the c-Abl/Arg inhibitor, PIP 2 .…”

Section: C-abl/arg Regulationmentioning

confidence: 99%

“…[45][46][47] Activation of nuclear c-Abl by DNA-damaging agents c-Abl and Arg during solid tumor progression / Ganguly and Plattner M Monographs induces G1 arrest and/or apoptosis, [48][49][50][51][52][53][54] whereas activation of the membrane and cytoplasmic pools of c-Abl and Arg by growth factors promotes membrane ruffling and motility of fibroblasts and endothelial cells, as well as endothelial tubule formation. 6,10,22,33,36,[55][56][57][58][59][60][61] In contrast, inhibition or knockout of c-Abl promotes wound-healing motility and migration toward collagen, fibronectin, or insulin. 62,63 c-Abl kinase activity decreases following detachment of fibroblasts from the extracellular matrix, and adhesion to fibronectin transiently increases c-Abl activity; induces its export from the nucleus to focal contacts, 64 which prevents cell spreading and promotes the formation of F-actin microspikes and filopodia.…”

Section: Biological Function Of C-abl/arg In Nontransformed Cellsmentioning

confidence: 99%

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

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Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/ or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/ Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

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Cooperative Interactions Between Integrins and Growth Factor Signaling in Pathological Angiogenesis

Roth¹,

Tweedie²,

Brooks

2010

The Tumor Microenvironment

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Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor– and Vascular Endothelial Growth Factor–induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis

Cited by 42 publications

References 45 publications

c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 and by disruption of actin

c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 and by disruption of actin

Activation of Abl Family Kinases in Solid Tumors

Cooperative Interactions Between Integrins and Growth Factor Signaling in Pathological Angiogenesis

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