Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis

Shen, Tang‐Long; Park, Ann Y.J.; Alcaraz, Ana; Xu, Peng; Jang, Ihn Kyung; Koni, Pandelakis A.; Flavell, Richard A.; Gu, Hua; Guan, Jun

doi:10.1083/jcb.200411155

Cited by 266 publications

(319 citation statements)

References 42 publications

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“…They are immediately activated by integrin ligation and play a role in growth factor-mediated angiogenesis. 20,21 For these reasons, we investigated whether Sema3A could regulate FAK and Src activation in endothelial cells stimulated with VEGF or bFGF. Consistent with our in vivo findings, Sema3A treatment of endothelial cells inhibited VEGFmediated phosphorylation of FAK at tyrosine 861 and Src at tyrosine 418 ( Figure 1B,D).…”

Section: Resultsmentioning

confidence: 99%

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Acevedo

Barillas

Weis

et al. 2008

Blood

193

213

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Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF-but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGFbut not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a functionblocking Nrp-1 antibody. While both Sema3A-and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF-but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.

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Section: Resultsmentioning

confidence: 99%

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Acevedo

Barillas

Weis

et al. 2008

Blood

193

213

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“…Our results indicate that Hic-5 contributes to these events in endothelial cells by bridging MT1-MMP and FAK. FAK is a well-known regulator of angiogenesis (Peng et al, 2004;Shen et al, 2005), as is MT1-MMP (Zhou et al, 2000;Chun et al, 2004;Stratman et al, 2009). Thus, defining molecular events that coordinate and regulate the activities of these key proteins will further refine our understanding of new blood vessel growth.…”

Section: Discussionmentioning

confidence: 99%

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Dave

Abbey

Duran

et al. 2016

Journal of Cell Science

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During angiogenesis, endothelial cells must coordinate matrix proteolysis with migration. Here, we tested whether the focal adhesion scaffold protein Hic-5 (also known as TGFB1I1) regulated endothelial sprouting in three dimensions. Hic-5 silencing reduced endothelial sprouting and lumen formation, and sprouting defects were rescued by the return of Hic-5 expression. Pro-angiogenic factors enhanced colocalization and complex formation between membrane type-1 matrix metalloproteinase (MT1-MMP, also known as MMP14) and Hic-5, but not between paxillin and MT1-MMP. The LIM2 and LIM3 domains of Hic-5 were necessary and sufficient for Hic-5 to form a complex with MT1-MMP. The degree of interaction between MT1-MMP and Hic-5 and the localization of the complex within detergent-resistant membrane fractions were enhanced during endothelial sprouting, and Hic-5 depletion lowered the surface levels of MT1-MMP. In addition, we observed that loss of Hic-5 partially reduced complex formation between MT1-MMP and focal adhesion kinase (FAK, also known as PTK2), suggesting that Hic-5 bridges MT1-MMP and FAK. Finally, Hic-5 LIM2-LIM3 deletion mutants reduced sprout initiation. Hic-5, MT1-MMP and FAK colocalized in angiogenic vessels during porcine pregnancy, supporting that this complex assembles during angiogenesis in vivo. Collectively, Hic-5 appears to enhance complex formation between MT1-MMP and FAK in activated endothelial cells, which likely coordinates matrix proteolysis and cell motility.

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“…However, FAK-/-p53-/-double knockout MEFs exhibited a strong cell migration defect, and this cell line became an established FAK-/-cells. Endothelial cell (EC) specific FAK knockouts also become early embryonic lethal due to vascular defects (Braren et al, 2006;Shen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Nuclear FAK: a New Mode of Gene Regulation from Cellular Adhesions

Lim

2013

Molecules and Cells

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Focal adhesion kinase (FAK) is a protein tyrosine kinase (PTK) crucial in regulation of cell migration and proliferation. In addition to its canonical roles as a cytoplasmic kinase downstream of integrin and growth factor receptor signaling, recent studies revealed new aspects of FAK action in the nucleus. Nuclear FAK promotes p53 and GATA4 degradation via ubiquitination, resulting in enhanced cell proliferation and reduced inflammatory responses. FAK can also serve as a co-transcriptional regulator that alters a gene transcriptional activity. These findings established a new paradigm of FAK signaling from cellular adhesions to the nucleus. Although physiological stimuli for controlling FAK nuclear localization have not been completely characterized, FAK shuttles from focal adhesions to the nucleus to directly convey extracellular signals. Interestingly, nuclear translocation of FAK becomes prominent in kinase-inhibited conditions such as in de-adhesion and pharmacological FAK inhibition, while a small fraction of nuclear FAK is observed a normal growth condition. In this review, roles of nuclear FAK in regulating transcription factors will be discussed. Furthermore, a potential use of a pharmacological FAK inhibitor to target nuclear FAK function in diseases such as inflammation will be emphasized.

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Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis

Cited by 266 publications

References 42 publications

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Nuclear FAK: a New Mode of Gene Regulation from Cellular Adhesions

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