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Actin-tethered junctional complexes in angiogenesis and lymphangiogenesis in association with vascular endothelial growth factor.

Zankov DP, Ogita H - Biomed Res Int (2015)

Bottom Line: Here we review involvement of actin cytoskeleton-associated junctional molecules of endothelial cells in angiogenesis and lymphangiogenesis.Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms.We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Shiga, Otsu 520-2192, Japan.

ABSTRACT
Vasculature is present in all tissues and therefore is indispensable for development, biology, and pathology of multicellular organisms. Endothelial cells guarantee proper function of the vessels and are the original component in angiogenesis. Morphogenesis of the vascular system utilizes processes like cell adhesion, motility, proliferation, and survival that are closely related to the dynamics of actin filaments and actin-tethered adhesion complexes. Here we review involvement of actin cytoskeleton-associated junctional molecules of endothelial cells in angiogenesis and lymphangiogenesis. Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms. Afadin mediates the pathways of vascular endothelial growth factor- (VEGF-) and sphingosine 1-phosphate-triggered angiogenesis and is essential for embryonic development of lymph vessels in mice. We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

No MeSH data available.


Related in: MedlinePlus

Proposed function of afadin in the VEGF or S1P receptor signaling during AG. In HUVECs, activated Rap1 (by still unknown mechanism) binds and recruits afadin to cell membrane where the complex between VEGF receptor, afadin, Rap1, and sequentially p85 and p110 subunits of PI3K assembles. Activated PI3K phosphorylates Akt and downstream signaling follows. Similar events occur after S1P receptor activation (not drawn). In addition, Rap1 stimulates different proteins (e.g., RAPL) that may contribute to proangiogenic signal.
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fig2: Proposed function of afadin in the VEGF or S1P receptor signaling during AG. In HUVECs, activated Rap1 (by still unknown mechanism) binds and recruits afadin to cell membrane where the complex between VEGF receptor, afadin, Rap1, and sequentially p85 and p110 subunits of PI3K assembles. Activated PI3K phosphorylates Akt and downstream signaling follows. Similar events occur after S1P receptor activation (not drawn). In addition, Rap1 stimulates different proteins (e.g., RAPL) that may contribute to proangiogenic signal.

Mentions: VEGF signaling is also critical for tumor AG. At present the most extensively applied medication in human cancer treatment is VEGF inhibitors [40]. One of the downstream targets of activated VEGF receptor is Rap1 GTPase that is also indispensable for the vessel formation [41]. In epithelial cells Rap1 associates with afadin and recruits epithelial (E)-cadherin to adherens junctions [42]. Understanding of the partners of activated Rap1 in ECs had not been extensive when we investigated Rap1-driven mechanisms in VEGF and sphingosine 1-phosphate- (S1P-) induced AG [43]. By studying VEGF- or S1P-stimulated human umbilical vein ECs (HUVECs) and conditional knockout (cKO) mice with endothelial-specific afadin gene disruption, we found that (i) in HUVECs, intracellular localization of afadin was Rap1-dependent and colocalization of activated (GTP-containing) Rap1 and afadin was observed in the cell-cell contacts and the leading edge of polarized moving cells; (ii) afadin or Rap1 knockdown in HUVECs reduced VEGF- or S1P-stimulated capillary-like network formation in Matrigel and 3D gels, suppressed migration and proliferation of HUVECs, and increased the number of apoptotic cells; (iii) equivalent to the epithelial cells, Rap1 and afadin played key roles in accumulation of adherens and tight junction proteins since absence of afadin or Rap1 in HUVECs removed the fluorescent signal in the cell membrane for nectin-2, VE-cadherin, claudin-5, and junctional adhesion molecule A; (iv) in VEGF- or S1P-stimulated HUVECs, afadin and Rap1 controlled specifically phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) but not extracellular signal-regulated kinase or p38. The subsequent experiments revealed that afadin is essential for the interaction between phosphoinositide 3-kinase (PI3K) regulatory subunit p85 and VEGF or S1P receptors. That interaction recruits catalytic subunit p110 of PI3K and Akt/eNOS phosphorylation follows (schematically drawn in Figure 2). Akt/eNOS signaling is proangiogenic and downstream of VEGF and S1P in ECs [44, 45].


Actin-tethered junctional complexes in angiogenesis and lymphangiogenesis in association with vascular endothelial growth factor.

Zankov DP, Ogita H - Biomed Res Int (2015)

Proposed function of afadin in the VEGF or S1P receptor signaling during AG. In HUVECs, activated Rap1 (by still unknown mechanism) binds and recruits afadin to cell membrane where the complex between VEGF receptor, afadin, Rap1, and sequentially p85 and p110 subunits of PI3K assembles. Activated PI3K phosphorylates Akt and downstream signaling follows. Similar events occur after S1P receptor activation (not drawn). In addition, Rap1 stimulates different proteins (e.g., RAPL) that may contribute to proangiogenic signal.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4389985&req=5

fig2: Proposed function of afadin in the VEGF or S1P receptor signaling during AG. In HUVECs, activated Rap1 (by still unknown mechanism) binds and recruits afadin to cell membrane where the complex between VEGF receptor, afadin, Rap1, and sequentially p85 and p110 subunits of PI3K assembles. Activated PI3K phosphorylates Akt and downstream signaling follows. Similar events occur after S1P receptor activation (not drawn). In addition, Rap1 stimulates different proteins (e.g., RAPL) that may contribute to proangiogenic signal.
Mentions: VEGF signaling is also critical for tumor AG. At present the most extensively applied medication in human cancer treatment is VEGF inhibitors [40]. One of the downstream targets of activated VEGF receptor is Rap1 GTPase that is also indispensable for the vessel formation [41]. In epithelial cells Rap1 associates with afadin and recruits epithelial (E)-cadherin to adherens junctions [42]. Understanding of the partners of activated Rap1 in ECs had not been extensive when we investigated Rap1-driven mechanisms in VEGF and sphingosine 1-phosphate- (S1P-) induced AG [43]. By studying VEGF- or S1P-stimulated human umbilical vein ECs (HUVECs) and conditional knockout (cKO) mice with endothelial-specific afadin gene disruption, we found that (i) in HUVECs, intracellular localization of afadin was Rap1-dependent and colocalization of activated (GTP-containing) Rap1 and afadin was observed in the cell-cell contacts and the leading edge of polarized moving cells; (ii) afadin or Rap1 knockdown in HUVECs reduced VEGF- or S1P-stimulated capillary-like network formation in Matrigel and 3D gels, suppressed migration and proliferation of HUVECs, and increased the number of apoptotic cells; (iii) equivalent to the epithelial cells, Rap1 and afadin played key roles in accumulation of adherens and tight junction proteins since absence of afadin or Rap1 in HUVECs removed the fluorescent signal in the cell membrane for nectin-2, VE-cadherin, claudin-5, and junctional adhesion molecule A; (iv) in VEGF- or S1P-stimulated HUVECs, afadin and Rap1 controlled specifically phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) but not extracellular signal-regulated kinase or p38. The subsequent experiments revealed that afadin is essential for the interaction between phosphoinositide 3-kinase (PI3K) regulatory subunit p85 and VEGF or S1P receptors. That interaction recruits catalytic subunit p110 of PI3K and Akt/eNOS phosphorylation follows (schematically drawn in Figure 2). Akt/eNOS signaling is proangiogenic and downstream of VEGF and S1P in ECs [44, 45].

Bottom Line: Here we review involvement of actin cytoskeleton-associated junctional molecules of endothelial cells in angiogenesis and lymphangiogenesis.Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms.We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Shiga, Otsu 520-2192, Japan.

ABSTRACT
Vasculature is present in all tissues and therefore is indispensable for development, biology, and pathology of multicellular organisms. Endothelial cells guarantee proper function of the vessels and are the original component in angiogenesis. Morphogenesis of the vascular system utilizes processes like cell adhesion, motility, proliferation, and survival that are closely related to the dynamics of actin filaments and actin-tethered adhesion complexes. Here we review involvement of actin cytoskeleton-associated junctional molecules of endothelial cells in angiogenesis and lymphangiogenesis. Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms. Afadin mediates the pathways of vascular endothelial growth factor- (VEGF-) and sphingosine 1-phosphate-triggered angiogenesis and is essential for embryonic development of lymph vessels in mice. We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

No MeSH data available.


Related in: MedlinePlus