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Tyrosine Phosphorylation and Endothelial Cell Barrier Regulation

  • Alexander D. Verin
    Correspondence
    Address reprint requests to Alexander D. Verin, Ph.D., The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, 5A.50B, Baltimore, MD 21224-6801
    Affiliations
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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      In this issue of The American Journal of Pathology, Sui and co-authors
      • Sui XF
      • Kiser TD
      • Hyun SW
      • Angelini DJ
      • Del Vecchio RL
      • Yong BA
      • Hasday JD
      • Romer LH
      • Passaniti A
      • Tonks NK
      • Goldblum SE
      Receptor protein tyrosine phosphatase μ regulates the paracellular pathway in human lung microvascular endothelia.
      evaluate the involvement of protein Tyr phosphatase (PTPase) μ in the regulation of zonula adherens (ZA) multiprotein complexes and endothelial cell (EC) paracellular permeability. They demonstrate that PTPase μ expression is almost completely restricted to the sites of cell-cell contacts in postconfluent pulmonary ECs, and this expression is required for EC barrier function. They also demonstrate that PTPase μ and VE-cadherin interact at cell borders where PTPase μ decreases tyrosine phosphorylation of VE-cadherin. These studies identify a link between PTPase μ-mediated VE-cadherin phosphorylation and EC permeability. The significance of these findings as they relate to phosphorylation in maintenance of the EC barrier is discussed below.
      Inflammatory diseases of the lung are characterized by increases in vascular permeability and enhanced leukocyte infiltration reflecting compromise of the semi-selective EC barrier that controls the movement of fluids, macromolecules, and leukocytes between vascular compartments and the interstitium.
      • Groeneveld AB
      Vascular pharmacology of acute lung injury and acute respiratory distress syndrome.
      • Dudek SM
      • Garcia JG
      Cytoskeletal regulation of pulmonary vascular permeability.
      Paracellular EC permeability is regulated by a balance between contractile (centripetal cytoskeletal tension) and opposing tethering (cell-cell and cell-matrix adhesion) forces and is dependent on multiple signaling events including protein phosphorylation and/or protein translocation to specific intracellular locations.
      • Dudek SM
      • Garcia JG
      Cytoskeletal regulation of pulmonary vascular permeability.
      • Yuan SY
      Protein kinase signaling in the modulation of microvascular permeability.
      A considerable body of evidence now supports a role for tyrosine phosphorylation in the regulation of vascular permeability.
      • Bogatcheva NV
      • Garcia JG
      • Verin AD
      Role of tyrosine kinase signaling in endothelial cell barrier regulation.
      For example, genistein, a general tyrosine kinase inhibitor, significantly decreases basal albumin permeability in cultured pulmonary EC monolayers.
      • Shi S
      • Verin AD
      • Schaphorst KL
      • Gilbert-McClain LI
      • Patterson CE
      • Irwin RP
      • Natarajan V
      • Garcia JG
      Role of tyrosine phosphorylation in thrombin-induced endothelial cell contraction and barrier function.
      In contrast, 2,5 DHC (methyl-2,5-dihydroxycinnamate), a potent inhibitor of receptor tyrosine kinases, produces decreased transendothelial electrical resistance indicative of EC barrier compromise.
      • Shi S
      • Verin AD
      • Schaphorst KL
      • Gilbert-McClain LI
      • Patterson CE
      • Irwin RP
      • Natarajan V
      • Garcia JG
      Role of tyrosine phosphorylation in thrombin-induced endothelial cell contraction and barrier function.
      Some tyrphostins, members of a family of specific tyrosine kinase inhibitors, selectively disrupt either cell-cell junctions or cell-substrate attachments, or both, whereas others have no effect on the EC cytoskeleton.
      • Farooki AZ
      • Epstein DL
      • O'Brien ET
      Tyrphostins disrupt stress fibers and cellular attachments in endothelial monolayers.
      This study also suggests that some basal level of tyrosine phosphorylation is necessary to maintain EC barrier integrity. Collectively, the wide spectrum of the cellular effects of tyrosine kinase inhibitors suggests that specific tyrosine kinases may be involved in the regulation of endothelial barrier properties in a complex manner in defined subcellular compartments.
      Several edemagenic agents, including thrombin, vascular endothelial growth factor, and histamine, stimulate protein tyrosine phosphorylation in EC, which correlates with an increase in permeability.
      • Bogatcheva NV
      • Garcia JG
      • Verin AD
      Role of tyrosine kinase signaling in endothelial cell barrier regulation.
      It is well established that thrombin-induced EC barrier dysfunction is critically dependent on increased levels of myosin light chain (MLC) phosphorylation, which results in stress fiber formation and increased contraction.
      • Dudek SM
      • Garcia JG
      Cytoskeletal regulation of pulmonary vascular permeability.
      • Bogatcheva NV
      • Garcia JG
      • Verin AD
      Molecular mechanisms of thrombin-induced endothelial cell permeability.
      This process is controlled, at least in part, via activation of calcium/calmodulin-dependent MLC kinase (MLCK).
      • Garcia JG
      • Davis HW
      • Patterson CE
      Regulation of endothelial cell gap formation and barrier dysfunction: role of myosin light chain phosphorylation.
      • Goeckeler ZM
      • Wysolmerski RB
      Myosin light chain kinase-regulated endothelial cell contraction: the relationship between isometric tension, actin polymerization, and myosin phosphorylation.
      At the same time thrombin-induced EC barrier dysfunction occurs in association with thrombin-induced EC protein tyrosine phosphorylation, increased total tyrosine kinase activity in EC homogenates, and rapid translocation of nonreceptor tyrosine kinase, p60src to the cytoskeleton.
      • Shi S
      • Verin AD
      • Schaphorst KL
      • Gilbert-McClain LI
      • Patterson CE
      • Irwin RP
      • Natarajan V
      • Garcia JG
      Role of tyrosine phosphorylation in thrombin-induced endothelial cell contraction and barrier function.
      • Marsen TA
      • Simonson MS
      • Dunn MJ
      Thrombin-mediated ET-1 gene regulation involves CaM kinases and calcineurin in human endothelial cells.
      Genistein significantly attenuates p60src tyrosine kinase activity, thrombin-induced MLC phosphorylation, and the associated increase in permeability,
      • Shi S
      • Verin AD
      • Schaphorst KL
      • Gilbert-McClain LI
      • Patterson CE
      • Irwin RP
      • Natarajan V
      • Garcia JG
      Role of tyrosine phosphorylation in thrombin-induced endothelial cell contraction and barrier function.
      suggesting a link between thrombin-induced contraction and permeability and p60src activation.
      Recent studies demonstrate that p60src may be involved in the regulation of EC permeability in several distinct ways. Studies of the novel EC MLCK have identified sites of p60src tyrosine phosphorylation in the unique N-terminus of one EC MLCK isoform (EC MLCK-1).
      • Birukov KG
      • Csortos C
      • Marzilli L
      • Dudek S
      • Ma SF
      • Bresnick AR
      • Verin AD
      • Cotter RJ
      • Garcia JG
      Differential regulation of alternatively spliced endothelial cell myosin light chain kinase isoforms by p60(Src).
      Phosphorylation of EC MLCK-1 by purified p60src results in a twofold to threefold increase in MLCK activity.
      • Birukov KG
      • Csortos C
      • Marzilli L
      • Dudek S
      • Ma SF
      • Bresnick AR
      • Verin AD
      • Cotter RJ
      • Garcia JG
      Differential regulation of alternatively spliced endothelial cell myosin light chain kinase isoforms by p60(Src).
      MLCK activation is linked to increased MLCK tyrosine phosphorylation and increased stable association of MLCK with p60src
      • Garcia JG
      • Verin AD
      • Schaphorst K
      • Siddiqui R
      • Patterson CE
      • Csortos C
      • Natarajan V
      Regulation of endothelial cell myosin light chain kinase by Rho, cortactin, and p60(src).
      • Shi S
      • Garcia JG
      • Roy S
      • Parinandi NL
      • Natarajan V
      Involvement of c-Src in diperoxovanadate-induced endothelial cell barrier dysfunction.
      in pulmonary ECs, implicating MLCK as a cytoskeletal target for p60src in vivo. In addition, cortactin, a p60src substrate and F-actin binding protein, is present in the p60src-MLCK complex in ECs stimulated with diperoxivanadate, a potent stimulator of tyrosine phosphorylation.
      • Garcia JG
      • Verin AD
      • Schaphorst K
      • Siddiqui R
      • Patterson CE
      • Csortos C
      • Natarajan V
      Regulation of endothelial cell myosin light chain kinase by Rho, cortactin, and p60(src).
      Diperoxivanadate-induced cortactin tyrosine phosphorylation is associated with cortactin translocation to the actin cytoskeleton.
      • Garcia JG
      • Verin AD
      • Schaphorst K
      • Siddiqui R
      • Patterson CE
      • Csortos C
      • Natarajan V
      Regulation of endothelial cell myosin light chain kinase by Rho, cortactin, and p60(src).
      Translocation of tyrosine-phosphorylated cortactin to the cytoskeletal fraction is also observed in thrombin-activated platelets.
      • Ozawa K
      • Kashiwada K
      • Takahashi M
      • Sobue K
      Translocation of cortactin (p80/85) to the actin-based cytoskeleton during thrombin receptor-mediated platelet activation.
      Cortactin co-localization with actin peripheral structures, such as membrane ruffles and lamellopodia, is found in several cell types
      • Wu H
      • Parsons JT
      Cortactin, an 80/85-kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex.
      and may be an important regulator of cortical actin assembly/disassembly. A recent study by Dudek and colleagues
      • Dudek SM
      • Jacobson JR
      • Chiang ET
      • Birukov KG
      • Wang P
      • Zhan X
      • Garcia JG
      Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase.
      indicated that p60src-mediated tyrosine phosphorylation of cortactin, as well as binding of this protein to EC MLCK, is important for actin remodeling induced by sphingosine 1-phosphate, a potent EC barrier-enhancing agent.
      • Dudek SM
      • Jacobson JR
      • Chiang ET
      • Birukov KG
      • Wang P
      • Zhan X
      • Garcia JG
      Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase.
      Accordingly, depending on the stimulus and subcellular localization, p60src-mediated tyrosine phosphorylation of cortactin and MLCK may be associated with either increased EC permeability or EC barrier enhancement.
      Little is known about the role of tyrosine dephosphorylation in the regulation of EC barrier function. Vanadate, a potent and specific inhibitor of PTPases, increases basal and thrombin-induced MLC phosphorylation in pulmonary EC
      • Gilbert-McClain LI
      • Verin AD
      • Shi S
      • Irwin RP
      • Garcia JG
      Regulation of endothelial cell myosin light chain phosphorylation and permeability by vanadate.
      implicating the involvement of PTPase activity in the regulation of EC contraction. However, PTPases involved in the regulation of MLC phosphorylation have never been identified.
      PTPase inhibitors also increase the level of tyrosine phosphorylation of specific target proteins present at cellular boundaries. This increase in tyrosine phosphorylation at the sites of cell-cell contacts correlates with an increase in paracellular permeability,
      • Staddon JM
      • Herrenknecht K
      • Smales C
      • Rubin LL
      Evidence that tyrosine phosphorylation may increase tight junction permeability.
      • Young BA
      • Sui X
      • Kiser TD
      • Hyun SW
      • Wang P
      • Sakarya S
      • Angelini DJ
      • Schaphorst KL
      • Hasday JD
      • Cross AS
      • Romer LH
      • Passaniti A
      • Goldblum SE
      Protein tyrosine phosphatase activity regulates endothelial cell-cell interactions, the paracellular pathway, and capillary tube stability.
      implicating the involvement of PTPases in the regulation of cell-cell adhesion. Homophilic endothelial cell-cell adhesion is determined primarily by the function of VE-cadherin, the main component of ZA, a junctional complex, which is tethered to actin microfilaments.
      • Dejana E
      • Corada M
      • Lampugnani MG
      Endothelial cell-to-cell junctions.
      • Bazzoni G
      • Dejana E
      Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.
      Some evidence suggests that the phosphorylation state of VE-cadherin may affect EC permeability.
      • Dejana E
      • Corada M
      • Lampugnani MG
      Endothelial cell-to-cell junctions.
      • Esser S
      • Lampugnani MG
      • Corada M
      • Dejana E
      • Risau W
      Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells.
      • Nwariaku FE
      • Liu Z
      • Zhu X
      • Turnage RH
      • Sarosi GA
      • Terada LS
      Tyrosine phosphorylation of vascular endothelial cadherin and the regulation of microvascular permeability.
      ZA function is also regulated by accessory catenin proteins with junction formation accompanied by tyrosine dephosphorylation of these proteins, correlating with the strength and stability of these junctions.
      • Lampugnani MG
      • Corada M
      • Andriopoulou P
      • Esser S
      • Risau W
      • Dejana E
      Cell confluence regulates tyrosine phosphorylation of adherens junction components in endothelial cells.
      Histamine-induced phosphorylation of VE-cadherin, α/β-catenins, and plakoglobin (γ-catenin) correlates with dissociation of VE-cadherin from the actin cytoskeleton.
      • Andriopoulou P
      • Navarro P
      • Zanetti A
      • Lampugnani MG
      • Dejana E
      Histamine induces tyrosine phosphorylation of endothelial cell-to-cell adherens junctions.
      A time course of diperoxivanadate-induced phosphorylation of β/γ-catenins correlates well with diperoxivanadate-induced decreases in transendothelial electrical resistance.
      • Garcia JG
      • Schaphorst KL
      • Verin AD
      • Vepa S
      • Patterson CE
      • Natarajan V
      Diperoxovanadate alters endothelial cell focal contacts and barrier function: role of tyrosine phosphorylation.
      Thrombin-induced tyrosine phosphorylation of β/γ and p120-catenins correlates with the phosphorylation and dissociation of the PTPase SHP2 from cadherin-catenins complexes, where this enzyme is presented in quiescent cells,
      • Ukropec JA
      • Hollinger MK
      • Salva SM
      • Woolkalis MJ
      SHP2 association with VE-cadherin complexes in human endothelial cells is regulated by thrombin.
      suggesting that SHP2 could be one of the PTPases regulating levels of phosphorylation of ZA proteins in endothelium.
      Several other PTPases associated with ZA and able to dephosphorylate ZA proteins have been identified in various cell types.
      • Balsamo J
      • Leung T
      • Ernst H
      • Zanin MK
      • Hoffman S
      • Lilien J
      Regulated binding of PTP1B-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of beta-catenin.
      • Brady-Kalnay SM
      • Rimm DL
      • Tonks NK
      Receptor protein tyrosine phosphatase PTPμ associates with cadherins and catenins in vivo.
      • Nawroth R
      • Poell G
      • Ranft A
      • Kloep S
      • Samulowitz U
      • Fachinger G
      • Golding M
      • Shima DT
      • Deutsch U
      • Vestweber D
      VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts.
      • Holsinger LJ
      • Ward K
      • Duffield B
      • Zachwieja J
      • Jallal B
      The transmembrane receptor protein tyrosine phosphatase DEP1 interacts with p120(ctn).
      Of particular interest among them is PTPase μ. This receptor PTPase is highly expressed in the lung endothelium and localized almost exclusively at endothelial cell contact sites.
      • Fuchs M
      • Wang H
      • Ciossek T
      • Chen Z
      • Ullrich A
      Differential expression of MAM-subfamily protein tyrosine phosphatases during mouse development.
      • Bianchi C
      • Sellke FW
      • Del Vecchio RL
      • Tonks NK
      • Neel BG
      Receptor-type protein-tyrosine phosphatase μ is expressed in specific vascular endothelial beds in vivo.
      PTPase μ interacts with several cadherins
      • Brady-Kalnay SM
      • Rimm DL
      • Tonks NK
      Receptor protein tyrosine phosphatase PTPμ associates with cadherins and catenins in vivo.
      • Brady-Kalnay SM
      • Mourton T
      • Nixon JP
      • Pietz GE
      • Kinch M
      • Chen H
      • Brackenbury R
      • Rimm DL
      • Del Vecchio RL
      • Tonks NK
      Dynamic interaction of PTPμ with multiple cadherins in vivo.
      and may potentially be involved in the strengthening of endothelial cell-cell adhesion via maintenance of cadherins in a dephosphorylated state.
      In this issue of The American Journal of Pathology, Sui and co-authors
      • Sui XF
      • Kiser TD
      • Hyun SW
      • Angelini DJ
      • Del Vecchio RL
      • Yong BA
      • Hasday JD
      • Romer LH
      • Passaniti A
      • Tonks NK
      • Goldblum SE
      Receptor protein tyrosine phosphatase μ regulates the paracellular pathway in human lung microvascular endothelia.
      identify PTPase μ as a regulator of ZA multiprotein complexes and EC paracellular permeability. By immunofluorescence they demonstrate that PTPase μ expression is almost completely restricted to the sites of cell-cell contacts in postconfluent pulmonary EC. Using a siRNA technique, they show convincingly that specific depletion of PTPase μ significantly increases 14C-albumin flux across EC monolayers consistent with EC barrier dysfunction. Moreover, ectopic expression of wild-type PTPase μ, but not catalytically impaired mutants, enhanced EC barrier function in immortalized EC. To examine the molecular mechanisms involved in PTPase μ-mediated EC barrier preservation, the authors examined the interaction of PTPase μ with VE-cadherin in vivo and in vitro. They demonstrate that PTPase μ co-localized with VE-cadherin at cell borders. These proteins also co-immunoprecipitate under nondenaturing conditions, suggesting that they associated with each other in a functional complex. In addition, in vitro studies demonstrate that PTPase μ directly binds to VE-cadherin. Finally, ectopic expression of wild-type PTPase μ decreased tyrosine phosphorylation of VE-cadherin. Collectively, these elegant studies clearly demonstrate that PTPase μ is involved in EC barrier regulation and controls VE-cadherin phosphorylation, suggesting a link between PTPase μ-mediated VE-cadherin phosphorylation and EC permeability.
      The current study serves as an important contribution to our understanding of how tyrosine protein phosphorylation is involved in the regulation of EC barrier function. We now know that specific PTPases, such as PTP μ, are intimately involved in the regulation of cell-cell contacts and paracellular EC permeability. However, some important questions remain unanswered. For example, how does tyrosine phosphorylation at the C-terminal cytoplasmic domain of VE-cadherin (and other cadherins) affect homophilic adhesion provided by the extracellular portion of the molecule? How is dephosphorylation of ZA proteins, induced presumably by several PTPases, orchestrated in the cell? How do edemagenic agonists, such as thrombin or barrier-protective substances such as sphingosine 1-phosphate regulate PTPase activity? Further in vitro and in vivo studies are needed to evaluate the role of tyrosine protein phosphorylation, and specifically PTPase activity, in the regulation of EC permeability and vascular leak in the setting of both normal physiology and pathological conditions.

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