PUBLICATION

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

Authors
Wang, H., Lapek, J., Fujimura, K., Strnadel, J., Liu, B., Gonzalez, D.J., Zhang, W., Watson, F., Yu, V., Liu, C., Melo, C.M., Miller, Y.I., Elliott, K.C., Cheresh, D.A., Klemke, R.L.
ID
ZDB-PUB-180607-5
Date
2018
Source
Cell discovery   4: 26 (Journal)
Registered Authors
Klemke, Richard, Miller, Yury
Keywords
none
MeSH Terms
none
PubMed
29872538 Full text @ Cell Discov
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.
Genes / Markers
Figures
Figure Gallery (5 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
y1TgTransgenic Insertion
    y7TgTransgenic Insertion
      zf2170
        Small Deletion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        peak1MO1-peak1MRPHLNO
        peak1MO2-peak1MRPHLNO
        peak1TALEN1-peak1TALEN
        vegfaaMO1-vegfaaMRPHLNO
        1 - 4 of 4
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        Fish
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        1 - 1 of 1
        Show
        Mapping
        No data available