Endothelial
            <scp>FAK</scp>
            is required for tumour angiogenesis

Tavora, Bernardo; Batista, Sílvia; Reynolds, Louise E.; Jadeja, Shalini; Robinson, Stephen D.; Kostourou, Vassiliki; Hart, Ian R.; Fruttiger, Marcus; Parsons, Maddy; Hodivala‐Dilke, Kairbaan

doi:10.15252/emmm.201606907

Cited by 32 publications

(51 citation statements)

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“…Similarly, Chen et al (12) identified that the expression of FAK in hepatoma cells with a stronger migration and invasion ability was significantly higher than that in the hepatoma cells with weaker migration and invasion abilities. In the same study, the knockdown of FAK expression by siRNA affected the cellular migration of the hepatoma cells, a result also observed in human neuroblastoma (13) and melanoma (14) cells. The results of the present study also indicated that in the early migration process, reduced expression of FAK significantly decreased the number of lamellipodia.…”

Section: Discussionsupporting

confidence: 53%

Focal adhesion kinase is involved in the migration of human osteosarcoma cells

et al. 2015

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Abstract. The aim of the present study was to analyze the expression of focal adhesion kinase (FAK) in osteosarcoma (OS) cell lines with different migration abilities in order to determine the role of FAK in migration. A number of different 143B subclone cell lines (A1, A2, A3, A4 and A5) were obtained by a limiting dilution method, and the expression of FAK was detected using western blot analysis. The role of FAK in the migration of OS cells was investigated using small interfering RNA (siRNA), and the ratio of the number of lamellipodia was compared by immunofluorescence staining. The A2 and A3 OS 143B subclone cell lines demonstrated a stronger migration ability and exhibited higher FAK expression compared with the A1 cell line (P<0.05). Following transfection with FAK-siRNA, the migration ability of the A3 cells was significantly decreased (P<0.05), and the ratio of the number of lamellipodia formed was reduced from 35 to 11% (P<0.05). In conclusion, the level of FAK expression was higher in the cell lines with a stronger migration ability. FAK affects the migration ability of OS cells by suppressing the formation of lamellipodia.

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Section: Discussionsupporting

confidence: 53%

Focal adhesion kinase is involved in the migration of human osteosarcoma cells

et al. 2015

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“…Understanding the molecular mechanisms by which tumour blood vessels develop in vivo is necessary for a better understanding of the drivers of tumour angiogenesis. Focal adhesion kinase (FAK) is a 125‐kDa non‐receptor tyrosine kinase involved in tumour angiogenesis . Upon activation by various stimuli, including integrins and growth factors, FAK autophosphorylation at Y397 leads to binding and activation of Src, which in turn phosphorylates other FAK residues, including Y576, Y577, Y861, and Y925 .…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that Pdgfb‐iCre ert ‐inducible endothelial cell (EC)‐specific homozygous deletion of FAK leads to reduced primary tumour growth and angiogenesis . Other reports have indicated that hemizygous EC‐specific FAK kinase‐dead (KD) mice show no effect on primary tumour growth, but show reduced vascular endothelial growth factor (VEGF)‐stimulated vascular permeability and metastasis .…”

Section: Introductionmentioning

confidence: 99%

Focal Adhesion Kinase (FAK) tyrosine 397E mutation restores the vascular leakage defect in endothelium‐specific FAK‐kinase dead mice

Alexopoulou

Lees

Bodrug

et al. 2017

The Journal of Pathology

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Focal adhesion kinase (FAK) inhibitors have been developed as potential anticancer agents and are undergoing clinical trials. In vitro activation of the FAK kinase domain triggers autophosphorylation of Y397, Src activation, and subsequent phosphorylation of other FAK tyrosine residues. However, how FAK Y397 mutations affect FAK kinase‐dead (KD) phenotypes in tumour angiogenesis in vivo is unknown. We developed three Pdgfb‐iCreert‐driven endothelial cell (EC)‐specific, tamoxifen‐inducible homozygous mutant mouse lines: FAK wild‐type (WT), FAK KD, and FAK double mutant (DM), i.e. KD with a putatively phosphomimetic Y397E mutation. These ECCre+;FAKWT / WT, ECCre+;FAKKD / KD and ECCre+;FAKDM / DM mice were injected subcutaneously with syngeneic B16F0 melanoma cells. Tumour growth and tumour blood vessel functions were unchanged between ECCre+;FAKWT / WT and ECCre−;FAKWT / WT control mice. In contrast, tumour growth and vessel density were decreased in ECCre+;FAKKD / KD and ECCre+;FAKDM / DM mice, as compared with Cre − littermates. Despite no change in the percentage of perfused vessels or pericyte coverage in either genotype, tumour hypoxia was elevated in ECCre+;FAKKD / KD and ECCre+;FAKDM / DM mice. Furthermore, although ECCre+;FAKKD / KD mice showed reduced blood vessel leakage, ECCre+;FAKDM / DM and ECCre−;FAKDM / DM mice showed no difference in leakage. Mechanistically, fibronectin‐stimulated Y397 autophosphorylation was reduced in Cre+;FAKKD / KD ECs as compared with Cre+;FAKWT / WT cells, with no change in phosphorylation of the known Src targets FAK‐Y577, FAK‐Y861, FAK‐Y925, paxillin‐Y118, p130Cas‐Y410. Cre+;FAKDM / DM ECs showed decreased Src target phosphorylation levels, suggesting that the Y397E substitution actually disrupted Src activation. Reduced VE‐cadherin‐pY658 levels in Cre+;FAKKD / KD ECs were rescued in Cre+FAKDM / DM ECs, corresponding with the rescue in vessel leakage in the ECCre+;FAKDM / DM mice. We show that EC‐specific FAK kinase activity is required for tumour growth, angiogenesis, and vascular permeability. The ECCre+;FAKDM/DM mice restored the KD‐dependent tumour vascular leakage observed in ECCre+;FAKKD/KD mice in vivo. This study opens new fields in in vivo FAK signalling. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Treatment also of cancer cell lines with PF-228 at concentrations that significantly inhibited the phosphorylation of FAK failed to block cell growth, and instead, at least in some cancer cell lines, increased the cell growth (29). On the other hand, endothelial-specific loss of FAK in mice inhibited angiogenesis (65), whereas reduced levels of FAK in endothelial cells derived from FAKheterozygous mice led to increased proliferation and Akt activity levels (62). Notably, the angiogenesis and tumor growth were enhanced in FAK-heterozygous mice (62).…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110δ phosphoinositide‐3 kinase

2015

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The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is regulated by various mechanisms that are not fully understood. This includes regulation by Tyr phosphorylation by a mechanism that remains elusive. Here, we show that focal adhesion kinase (FAK) phosphorylates PTEN in vitro, in cell-free systems and in cells. Furthermore, by mass spectrometry, we identified Tyr336 on PTEN as being phosphorylated by FAK. Tyr336 phosphorylation increased phosphatase activity, protein-lipid interaction, and protein stability of PTEN. In cells, including primary mouse macrophages and human cancer cell lines, FAK was found to be negatively regulated by p110d phosphoinositide-3 kinase (PI3K), whereas the activation of FAK was positively regulated by RhoA-associated kinase (ROCK). Indeed, the phosphorylation of FAK was unexpectedly increased in macrophages derived from mice expressing kinase-dead p110d. Pharmacologic inactivation of RhoA/ROCK reduced the phosphorylation of FAK to normal levels in cells with genetically inactivated p110d. Likewise, pharmacologic inactivation of FAK reduced the phosphorylation of PTEN in cells expressing kinase-dead p110d and restored the functional defects of p110d inactivation, including Akt phosphorylation and cell proliferation. This work identifies FAK as a target of p110d PI3K that links RhoA with PTEN and establishes for the first time that PTEN is a substrate of FAK-mediated Tyr phosphorylation.-Tzenaki, N., Aivaliotis, M., Papakonstanti, E. A. Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110d phosphoinositide-3 kinase. FASEB J. 29, 4840-4852 (2015). www.fasebj.org

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Endothelial FAK is required for tumour angiogenesis

Cited by 32 publications

References 0 publications

Focal adhesion kinase is involved in the migration of human osteosarcoma cells

Focal adhesion kinase is involved in the migration of human osteosarcoma cells

Focal Adhesion Kinase (FAK) tyrosine 397E mutation restores the vascular leakage defect in endothelium‐specific FAK‐kinase dead mice

Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110δ phosphoinositide‐3 kinase

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