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Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase.

ABSTRACT: CD36 plays a critical role in the inhibition of angiogenesis through binding to the type 1 repeats of thrombospondin-1 (TSP-1) and activating Fyn tyrosine kinase and MAPK pathways. Here, we reveal a novel association of CD36 with VEGFR-2 and spleen tyrosine kinase (Syk). We also address the correlation between the expression of CD36 and Syk by demonstrating that overexpression of CD36 in HUVECs up-regulates endogenous Syk expression. We also define a new role for TSP-1 and CD36 in the activation of the VEGFR-2 signaling pathway that requires Syk. Our findings also identify a role for Syk as a stimulator of VEGF-A-induced angiogenesis by increasing phosphorylation of Y1175 in VEGFR-2, which is a major tyrosine for promoting VEGF-A-induced endothelial cell migration. Together, these studies introduce a new signaling pathway for TSP-1, CD36, and Syk, and address the role of these proteins in regulating the angiogenic switch.

SUBMITTER: Kazerounian S

PROVIDER: S-EPMC3099580 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase.

Kazerounian Shideh S Duquette Mark M Reyes Millys A MA Lawler James T JT Song Keli K Perruzzi Carole C Primo Luca L Khosravi-Far Roya R Bussolino Federico F Rabinovitz Isaac I Lawler Jack J

Blood 20110304 17

CD36 plays a critical role in the inhibition of angiogenesis through binding to the type 1 repeats of thrombospondin-1 (TSP-1) and activating Fyn tyrosine kinase and MAPK pathways. Here, we reveal a novel association of CD36 with VEGFR-2 and spleen tyrosine kinase (Syk). We also address the correlation between the expression of CD36 and Syk by demonstrating that overexpression of CD36 in HUVECs up-regulates endogenous Syk expression. We also define a new role for TSP-1 and CD36 in the activation ...[more]

PMID: 21378271

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Project description:BACKGROUND:Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation. METHODS:We used immunohistochemistry and immunoblotting to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq and phosphoproteomic mass spectrometry to investigate the SYK-regulated EGF-induced transcriptome and downstream substrates. FINDINGS:Induced expression of constitutively active SYK130E reduced cellular response to EGFR/ERBB2 inhibitor, lapatinib. Expression of EGFRWT, but not SYK non-phosphorylatable EGFR3F mutant, resulted in paclitaxel resistance, a phenotype characteristic to SYK active ovarian cancers. In tumor xenografts, SYK inhibitor reduces phosphorylation of EGFR substrates. Compared to SYKWT cells, SYKKO cells have an attenuated EGFR/ERBB2-transcriptional activity and responsiveness to EGF-induced transcription. In ovarian cancer tissues, pSYK (Y525/526) levels showed a positive correlation with pEGFR (Y1187). Intense immunoreactivity of pSYK (Y525/526) correlated with poor overall survival in ovarian cancer patients. INTERPRETATION:These findings indicate that SYK activity positively modulates the EGFR pathway, providing a biological foundation for co-targeting SYK and EGFR. FUND: Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, NIH/NCI, Ovarian Cancer Research Foundation Alliance, HERA Women's Cancer Foundation and Roseman Foundation. Funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript and eventually in the decision to submit the manuscript.

Project description:BackgroundPatients with cancer are at higher risk for venous thromboembolism (VTE) and bleeding, in turn complicating anticoagulant therapy. An added complexity is the toxicity profile of agents used to treat certain cancers, namely the vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), which are associated with both thromboembolism and hemorrhages. The purpose of this study was to evaluate whether patients taking concurrent VEGF TKI and therapeutic anticoagulant were at higher risk for bleeding compared with patients taking VEGF TKI alone.Materials and methodsThis was a single-center, retrospective chart review of patients who underwent treatment with a VEGF TKI with or without anticoagulant. The primary outcome included comparison of major bleeding rates between groups. Secondary outcomes included comparison of composite major and minor bleed rates and assessment of VTE incidence and recurrence among patients treated with a VEGF TKI and VEGF TKI plus anticoagulant, respectively.ResultsA total of 184 and 74 patients were included in the VEGF TKI alone and VEGF TKI + anticoagulant groups, respectively. Major bleeding events occurred in 6 of 184 patients (3.3%) and 6 of 74 patients (8.1%), respectively (p = .095). Composite major and minor bleeding events occurred in 22 of 184 (13.6%) and 17 of 74 (23%), respectively (p = .026). A total of 26 of 258 patients (10.1%) experienced a VTE event while taking a VEGF TKI, and 1 of 26 (3.8%) experienced a recurrent VTE event while taking a VEGF TKI plus anticoagulant.ConclusionPatients who received concomitant VEGF TKI plus anticoagulant had increased incidence of bleeding, although prospective studies are needed to further explore this association.Implications for practiceThe current study showed that use of concomitant vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI) and therapeutic anticoagulation was associated with an increased risk of composite bleeding events, although at comparable rates between patients treated with VEGF TKI plus direct oral anticoagulant (DOAC) versus VEGF TKI plus non-DOAC anticoagulant. This suggests that when anticoagulation is indicated in a patient receiving a VEGF TKI, the novel DOACs may be a safe alternative to historical anticoagulants (warfarin and enoxaparin). These results fill a gap in the literature and will help guide treatment decisions for patients requiring concurrent VEGF TKI and anticoagulation.

Dataset Information

Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase.

Publications

Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase.

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