Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription

Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription

Author Wang, Huawei Google Scholar
Lapek, John Google Scholar
Fujimura, Ken Google Scholar
Strnadel, Jan Google Scholar
Liu, Bei Google Scholar
Gonzalez, David J. Google Scholar
Zhang, Wei Google Scholar
Watson, Felicia Google Scholar
Yu, Vicky Google Scholar
Liu, Chao Google Scholar
Melo, Carina Muccilo Autor UNIFESP Google Scholar
Miller, Yury I. Google Scholar
Elliott, Kathryn C. Google Scholar
Cheresh, David A. Google Scholar
Klemke, Richard L. Google Scholar
Abstract PEAK1 is a newly described tyrosine kinase and scaffold protein that transmits integrin-mediated extracellular matrix (ECM) signals to facilitate cell movement and growth. While aberrant expression of PEAK1 has been linked to cancer progression, its normal physiological role in vertebrate biology is not known. Here we provide evidence that PEAK1 plays a central role in orchestrating new vessel formation in vertebrates. Deletion of the PEAK1 gene in zebrafish, mice, and human endothelial cells (ECs) induced severe defects in new blood vessel formation due to deficiencies in EC proliferation, survival, and migration. Gene transcriptional and proteomic analyses of PEAK1-deficient ECs revealed a significant loss of vascular endothelial growth factor receptor 2 (VEGFR2) mRNA and protein expression, as well as downstream signaling to its effectors, ERK, Akt, and Src kinase. PEAK1 regulates VEGFR2 expression by binding to and increasing the protein stability of the transcription factor GATA-binding protein 2 (GATA2), which controls VEGFR2 transcription. Importantly, PEAK1-GATA2-dependent VEGFR2 expression is mediated by EC adhesion to the ECM and is required for breast cancer-induced new vessel formation in mice. Also, elevated expression of PEAK1 and VEGFR2 mRNA are highly correlated in many human cancers including breast cancer. Together, our findings reveal a novel PEAK1-GATA2-VEGFR2 signaling axis that integrates cell adhesion and growth factor cues from the extracellular environment necessary for new vessel formation during vertebrate development and cancer.
Language English
Sponsor NIH
NCI
AHA
NIGMS/NIH
Ray Thomas Edwards Foundation
Grant number NIH: CA182495
NIH: CA184594
NIH: CA097022
NIH: HL135737
NIH: CA050286
NCI: CA180374
AHA: 16POST27250126
NIGMS/NIH: K12GM068524
Date 2018
Published in Cell Discovery. London, v. 4, p. -, 2018.
ISSN 2056-5968 (Sherpa/Romeo, impact factor)
Publisher Nature Publishing Group
Origin http://dx.doi.org/10.1038/s41421-018-0024-3
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000433282700001
URI http://repositorio.unifesp.br/handle/11600/46022

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