EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation

Brantley-Sieders, Dana M.; Caughron, Justin; Hicks, Donna J.; Pozzi, Ambra; Ruiz, Jenny; Chen, Jin

doi:10.1242/jcs.01061

Cited by 181 publications

(227 citation statements)

References 39 publications

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“…However, the lack of inactivating mutations of EPHA2 reported in this study indicates that EPHA2 functions in a manner unlike that of the other Eph receptor family members targeted by inactivating mutations. Furthermore, genetic amplification of EPHA2, albeit an uncommon finding in this study, correlates with its role as a putative oncogene for this tumor type in which it may promote angiogenesis [36], loss of growth control and contact inhibition [6,7]. Although the Eph family is among the largest receptor tyrosine kinase family in the human genome [37], the specific functions of each member remain incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

Mudali

Lakkur

et al. 2006

Clin Exp Metastasis

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EphA2 is a transmembrane receptor tyrosine kinase that functions in the regulation of cell growth, survival, angiogenesis, and migration and EphA2 targeting has been proposed as a novel therapeutic strategy for neoplasms that overexpress this protein. EphA2 overexpression has been correlated with increased invasive and metastatic ability in pancreatic cancer cell lines. However, the patterns of EphA2 expression in human pancreatic cancers and associated metastases is unknown, as are the genetics of EphA2 in this tumor type. We collected clinicopathologic data and paraffin-embedded materials from 98 patients with primary and/or metastatic pancreatic cancer and performed immunohistochemical labeling for EphA2 protein. EphA2 protein immunolabeling was found in 207 of 219 samples (95%). The expression was predominantly cytoplasmic, although predominant membranous staining was observed in a minority of cases. When evaluated specifically for labeling intensity, primary and metastatic carcinomas were more strongly positive compared to benign ducts and PanIN lesions (P < 0.00001 and P < 0.01, respectively) and poorly differentiated carcinomas were more strongly positive for EphA2 than well and moderately differentiated tumors (P < 0.005). When primary carcinomas without metastatic disease were specifically compared to carcinomas with associated metastatic disease, the advanced carcinomas showed relatively less strong positive labeling for EphA2 (P < 0.008). Moreover, decreased EphA2 labeling was more commonly found in liver (P < 0.002), lung (P < 0.004) or peritoneal metastases (P < 0.01) as compared to distant lymph node metastases (P < 0.01). Genetic sequencing of the tyrosine kinase domain of EPHA2 in 22 samples of xenograft enriched pancreatic cancer did not reveal any inactivating mutations. However, EPHA2 amplification was found in 1 of 33 pancreatic cancers corresponding to a lymph node metastasis, indicating EPHA2 genomic amplification may underlie EphA2 overexpression in a minority of patients. Our data confirms that EphA2 is overexpressed in pancreatic cancer, but suggests a relative loss of EphA2 in co-existent pancreatic cancer metastases as well as a role for EPHA2 in organ specific metastasis.

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Section: Discussionmentioning

confidence: 99%

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

Mudali

Lakkur

et al. 2006

Clin Exp Metastasis

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“…For kinase assay, wild-type and EphA2-deficient lung microvascular endothelial cells were isolated from EphA2 knockout mice (Brantley-Sieders et al, 2004a) and were infected with LZRS retrovirus expressing wild-type or W42 mutant form of EphA2 receptor. Parental and infected cells were serum starved for 24 h in serum-free Optimum medium followed by stimulation with ephrin-A1 (1 mg/ml).…”

Section: Plasmids Antibodies and Reagentsmentioning

confidence: 99%

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

et al. 2005

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Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligandinduced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.

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“…Together with integrin-associated signaling, Ephrins and Eph receptors mediate diverse activities such as effects on the actin cytoskeleton, cell-substrate adhesion, intercellular junctions, cell shape, and cell movement (16)(17)(18)(19). Ephrins and Eph receptors modulate the endothelial cellular assembly by controlling various signaling pathways (20). Ephrin receptors have also been shown to be the center of signaling crosstalk between integrins, PI3-K, and Rho-GTPases (21,22), which are also induced during KSHV infection (3).…”

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confidence: 99%

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

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

157

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Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (α3β1, αVβ3, and αVβ5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC-d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the α3β1, αVβ3, and xCT receptors, but not αVβ5. LR-translocated receptors were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated αVβ5 was polyubiquitinated, leading to clathrin-mediated entry that was targeted to lysosomes. Because the molecule(s) that integrate signal pathways and productive KSHV macropinocytosis were unknown, we immunoprecipitated KSHV-infected LR fractions with anti-α3β1 antibodies and analyzed them by mass spectrometry. The tyrosine kinase EphrinA2 (EphA2), implicated in many cancers, was identified in this analysis. EphA2 was activated by KSHV. EphA2 was also associated with KSHV and integrins (α3β1 and αVβ3) in LRs early during infection. Preincubation of virus with soluble EphA2, knockdown of EphA2 by shRNAs, or pretreatment of cells with anti-EphA2 monoclonal antibodies or tyrosine kinase inhibitor dasatinib significantly reduced KSHV entry and gene expression. EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. EphA2 shRNA ablated macropinocytosis-associated signaling events, virus internalization, and productive nuclear trafficking of KSHV DNA. Taken together, these studies demonstrate that the EphA2 receptor acts as a master assembly regulator of KSHV-induced signal molecules and KSHV entry in endothelial cells and suggest that the EphA2 receptor is an attractive target for controlling KSHV infection.virus entry | productive endocytosis | receptor tyrosine kinase

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EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation

Cited by 181 publications

References 39 publications

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

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