Type I Phosphatidylinositol Phosphate Kinase Beta Regulates Focal Adhesion Disassembly by Promoting β1 Integrin Endocytosis

Chao, Wei‐Ting; Ashcroft, Felicity; Daquinag, Alexes C.; Vadakkan, Tegy J.; Wei, Zhubo; Zhang, Pumin; Dickinson, Mary E.; Kunz, Jeannette

doi:10.1128/mcb.01207-09

Cited by 54 publications

(45 citation statements)

References 58 publications

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“…This microtubule-induced disassembly is characterized by integrin endocytosis at adhesion sites regulated by clathrin and specific clathrin adaptor proteins (Ezratty et al 2009); however, this pathway appears to be active on adhesions that reside in central regions of the cell. A recent report suggests that type I phosphatidylinositol kinase b (PIPKIb), which generates phosphatidylinositol-4,5-bisphosphate (PI4,5P 2 ) can also regulate internalization of active b1 integrins and focal adhesion turnover in motile cells (Chao et al 2010). Taken together, these studies support a key role for microtubule-mediated integrin internalization in the turnover of some focal adhesions.…”

Section: Turnover Of Adhesions In Protrusionssupporting

confidence: 61%

Integrins in Cell Migration

Huttenlocher¹,

Horwitz²

2011

Cold Spring Harbor Perspectives in Biology

634

566

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Integrin-based adhesion has served as a model for studying the central role of adhesion in migration. In this article, we outline modes of migration, both integrin-dependent and -independent in vitro and in vivo. We next discuss the roles of adhesion contacts as signaling centers and linkages between the ECM and actin that allows adhesions to serve as traction sites. This includes signaling complexes that regulate migration and the interplay among adhesion, signaling, and pliability of the substratum. Finally, we address mechanisms of adhesion assembly and disassembly and the role of adhesion in cellular polarity.

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Section: Turnover Of Adhesions In Protrusionssupporting

confidence: 61%

Integrins in Cell Migration

Huttenlocher¹,

Horwitz²

2011

Cold Spring Harbor Perspectives in Biology

634

566

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“…4a). Mechanisms of endocytosis were shown to contribute to the disassembly of focal adhesions during cell migration [8][9][10]17]. Therefore, we hypothesized that Brag2 may mediate endocytosis/internalization of b1-integrins in EC.…”

Section: Brag2 Promotes Endocytosis Of B1-integrins and Recycling Of mentioning

confidence: 99%

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

et al. 2014

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b1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated Brag2-silencing reduced EC angiogenic sprouting and migration. Brag2-siRNA transfection differentially affected a5b1-and aVb3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on b1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the aVb3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of a5b1-integrin, while reducing surface expression of aVb3-integrin. Mechanistically, Brag2-mediated aVb3-integrin-recycling and b1-integrin endocytosis and specifically of the active/matrix-bound a5b1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via b1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, b1-integrin endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Furthermore, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating b1-integrin internalization and link for the first time the process of b1-integrin endocytosis with angiogenesis.

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“…Next, to reduce the cellular PI(4,5)P 2 level, we silenced type I PIP5K (PIP5KI), which is a key regulator of PI(4,5)P 2 production. Three isoforms of PIP5KI have been identified, and among them, we focused on PIP5KI␤, which was recently reported to regulate focal adhesion disassembly by controlling ␤1 integrin trafficking (28). Transfection of PIP5KI␤ siRNAs successfully reduced PIP5KI␤ protein expression in endothelial cells (Fig.…”

Section: Pi(45)p 2 Is Required For Sema3e-induced Arf6mentioning

confidence: 99%

Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein

Sakurai

Jian

Lee

et al. 2011

Journal of Biological Chemistry

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The semaphorins are a family of secreted or membranebound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells. Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADPribosylation factor 6), which regulates intracellular trafficking of ␤1 integrin. However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells. We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrinmediated focal adhesions and endothelial cell collapse. Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration.Angiogenesis, the formation of new blood capillaries from pre-existing ones, is an essential process during embryonic development. In adults, angiogenesis is required for tissue repair during physiological wound healing, whereas dysregulated angiogenesis contributes to a variety of pathological conditions, such as diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and cancer (1). Hence, the identification of molecular mechanisms controlling normal and aberrant angiogenesis may afford new therapeutic opportunities for multiple human diseases (2). In this regard, recent studies revealed that axon guidance molecules, including netrin, slit, eph, and semaphorins, play a key role in developmental and postnatal angiogenesis (3). Among them, multiple secreted class III semaphorins (Sema3s) 4 are reported to control endothelial cell migration in vitro and in vivo (4 -7). Sema3s signal through A-type and D-type Plexin family proteins (Plexin-A1, -A2, and -A3 and Plexin-D1) and utilize their coreceptor neuropilins (Nrp1 and Nrp2) to tightly control proand antiangiogenic responses (8). However, the downstream signaling pathways initiated by these semaphorin receptors are complex and not fully understood,...

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Type I Phosphatidylinositol Phosphate Kinase Beta Regulates Focal Adhesion Disassembly by Promoting β1 Integrin Endocytosis

Cited by 54 publications

References 58 publications

Integrins in Cell Migration

Integrins in Cell Migration

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein

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