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

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.

A SNAI2-PEAK1-INHBA stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting subpopulations of tumor cells positive for antiapoptotic and stress signaling markers

“…This is consistent with both our observation that HER2-positive breast cancer cells xenografted with MSCs displayed increased expression of αSMA and vascular architecture in a PEAK1-dependent manner (Fig. 4c ) and recent work reporting a role for PEAK1 during developmental angiogenesis [ 43 ].…”

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

“…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. PEAK1 seems therefore to play roles in modulation of cell adhesion and growth factor cues from the extracellular environment necessary for new vessel formation during vertebrate development and cancer (Wang et al, 2018). PEAK1 has not been described as deiminated before.…”

Uterine Arteriovenous Malformation: A Pictorial Review of Diagnosis and Management

“…42 It also associates with p190RhoGAP to rule cell mobility and is linked to AKT to keep cells away from apoptosis. 43 Identifying the participation of RASA1 gives rise to the evolution of novel therapeutic approaches that help distinguish UAVM and other types of vascular malformations. 44 Moreover, PI3K/AKT and MEK are also vital pathways leading to cell growth and proliferation in UAVM lesions.…”

“…In addition, inhibition of the PI3K/AKT and Ras/MAP kinase pathways may also be effective gene therapy but is under study (Figure 16). [37][38][39][40][41][42][43][44][45][46][47][48]…”