Integrins and inside-out signal transduction: converging signals from PKC and PIP3

Kolanus, Waldemar; Seed, Brian

doi:10.1016/s0955-0674(97)80127-5

Cited by 124 publications

(80 citation statements)

References 77 publications

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“…Several reports have indicated that RhoA activity is required for agonist-induced ␤ 1 and ␤ 2 integrin activation in lymphoid cells (7,30). Likewise, a large body of experimental work has shown that PKC activation plays a central role in integrin function and integrin-cytoskeletal interactions (44,45). Our findings indicate that the selective inhibition of PKC in Th1 cells abolishes ␤ 1 integrin-dependent adhesion in response to chemokines and, as expected, to phorbol esters.…”

Section: Discussionsupporting

confidence: 78%

Chemokines Fail to Up-Regulate β1 Integrin-Dependent Adhesion in Human Th2 T Lymphocytes

Clissi¹,

D’Ambrosio

Geginat³

et al. 2000

The Journal of Immunology

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Th1 and Th2 cells are functionally distinct subsets of CD4+ T lymphocytes whose tissue-specific homing to sites of inflammation is regulated in part by the differential expression of P- and E-selectin ligands and selected chemokine receptors. Here we investigated the expression and function of β1 integrins in Th1 and Th2 cells polarized in vitro. Th1 lymphocytes adhere transiently to the extracellular matrix ligands laminin 1 and fibronectin in response to chemokines such as RANTES and stromal cell-derived factor-1, and this process is paralleled by the activation of the Rac1 GTPase and by a rapid burst of actin polymerization. Selective inhibitors of phosphoinositide-3 kinase prevent efficiently all of the above processes, whereas the protein kinase C inhibitor bisindolylmaleimide prevents chemokine-induced adhesion without affecting Rac1 activation and actin polymerization. Notably, chemokine-induced adhesion to β1 integrin ligands is markedly reduced in Th2 cells. Such a defect cannot be explained by a reduced sensitivity to chemokine stimulation in this T cell subset, nor by a defective activation of the signaling cascade involving phosphoinositide-3 kinase, Rac1, and actin turnover, as all these processes are activated at comparable levels by chemokines in the two subsets. We propose that reduced β1 integrin-mediated adhesion in Th2 cells may restrain their ability to invade and/or reside in sites of chronic inflammation, which are characterized by thickening of basement membranes and extensive fibrosis, requiring efficient interaction with organized extracellular matrices.

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Section: Discussionsupporting

confidence: 78%

Chemokines Fail to Up-Regulate β1 Integrin-Dependent Adhesion in Human Th2 T Lymphocytes

Clissi¹,

D’Ambrosio

Geginat³

et al. 2000

The Journal of Immunology

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“…1A). We previously demonstrated that the inserted PH domain binds to phosphoinositides including phosphatidylinositol 4,5-diphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate (PIP3) (20), both of which are known regulators of integrin-mediated cell adhesion (21,22). However, the structural basis for the phosphoinositide/kindlin PH recognition and how it may regulate the kindlin function remain elusive.…”

Section: Kindlins Are a Subclass Of Ferm-containing Proteins That Havmentioning

confidence: 99%

Structural Basis of Phosphoinositide Binding to Kindlin-2 Protein Pleckstrin Homology Domain in Regulating Integrin Activation

Liu

Fukuda

et al. 2011

Journal of Biological Chemistry

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Background: Kindlin-2 is a key regulator of integrin activation. Results: Kindlin-2 contains a PH domain with a distinct binding pocket for phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) that promotes talin-mediated integrin activation. Conclusion: PIP3-mediated membrane binding of kindlin-2 is crucial for the cooperation of kindlin-2 with talin in activating integrin. Significance: Learning how kindlin-2 functions is crucial for understanding the integrin-mediated cell adhesion.

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“…3A). To demonstrate the functionality of EP 2 and EP 4 receptors, we performed adhesion assays in the absence or presence of butaprost, a selective EP 2 receptor agonist, and PGE 1 alcohol, a selective EP 4 receptor agonist. Both agonists accelerated HUVEC adhesion to gelatin with similar kinetics as observed for PGE 2 (Fig.…”

Section: Pgementioning

confidence: 99%

“…Integrins are the main receptors for extracellular matrix proteins and consist of two non-covalently associated ␣ and ␤ subunits (3). Integrin ligand binding affinity and adhesion-promoting activity are regulated by intracellular events ("inside out" signaling) (4). Upon ligand binding, integrins rapidly cluster and recruit structural (e.g.…”

mentioning

confidence: 99%

Prostaglandin E2 Promotes Integrin αVβ3-dependent Endothelial Cell Adhesion, Rac-activation, and Spreading through cAMP/PKA-dependent Signaling

Dormond¹,

Bezzi

Mariotti

et al. 2002

Journal of Biological Chemistry

142

108

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We have recently reported that the inhibition of endothelial cell COX-2 by non-steroidal anti-inflammatory drugs suppresses ␣ V ␤ 3 -(but not ␣ 5 ␤ 1 -) dependent Rac activation, endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047). Here we investigated the role of the COX-2 metabolites PGE 2 and TXA2 in regulating human umbilical vein endothelial cell (HUVEC) adhesion and spreading. We report that PGE 2 accelerated ␣ V ␤ 3 -mediated HUVEC adhesion and promoted Rac activation and cell spreading, whereas the TXA2 agonist U46619 retarded adhesion and inhibited spreading. We show that the cAMP level and the cAMP-regulated protein kinase A (PKA) activity are critical mediators of these PGE 2 effects. ␣ V ␤ 3 -mediated adhesion induced a transient COX-2-dependent rise in cAMP levels, whereas the cellpermeable cAMP analogue 8-brcAMP accelerated adhesion, promoted Rac activation, and cell spreading in the presence of the COX-2 inhibitor NS-398. Pharmacological inhibition of PKA completely blocked ␣ V ␤ 3 -mediated adhesion. A constitutively active Rac mutant (L61Rac) rescued ␣ V ␤ 3 -dependent spreading in the presence of NS398 or U46691, but did not accelerate adhesion, whereas a dominant negative Rac mutant (N17Rac) suppressed spreading without affecting adhesion. ␣ 5 ␤ 1 -mediated HU-VEC adhesion, Rac activation, and spreading were not affected by PGE 2 , U46691, 8-brcAMP, or the inhibition of PKA. In conclusion, these results demonstrate that PGE 2 accelerates ␣ V ␤ 3 -mediated endothelial cell adhesion through cAMP-dependent PKA activation and induces ␣ V ␤ 3 -dependent spreading via cAMP-and PKA-dependent Rac activation and may contribute to the further understanding of the regulation of vascular integrins ␣ V ␤ 3 by COX-2/PGE 2 during tumor angiogenesis and inflammation.Tumor angiogenesis, i.e. the formation of new blood vessels in response to angiogenic stimuli, promotes tumor progression by stimulating tumor cell survival, tumor invasion, and metastasis formation (1). Many molecules involved in mediating or regulating angiogenesis have been identified (2). They include growth factors (i.e. vascular endothelial growth factors, VEGF) 1 and their cell surface receptors, matrix-degrading enzymes (e.g. matrix metalloproteinases), vascular remodeling ligands, and receptors (i.e. angiopoietins and Tie receptors) and adhesion receptors of the integrin and cadherin families. Integrins are the main receptors for extracellular matrix proteins and consist of two non-covalently associated ␣ and ␤ subunits (3). Integrin ligand binding affinity and adhesion-promoting activity are regulated by intracellular events ("inside out" signaling) (4). Upon ligand binding, integrins rapidly cluster and recruit structural (e.g. ␣-actinin, talin, vinculin) and signaling (e.g. focal adhesion kinase, paxillin, c-Src) proteins to form characteristic structures called focal contacts or focal adhesions (5). Integrins and focal adhesions propagate tensional ...

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Integrins and inside-out signal transduction: converging signals from PKC and PIP3

Cited by 124 publications

References 77 publications

Chemokines Fail to Up-Regulate β1 Integrin-Dependent Adhesion in Human Th2 T Lymphocytes

Chemokines Fail to Up-Regulate β1 Integrin-Dependent Adhesion in Human Th2 T Lymphocytes

Structural Basis of Phosphoinositide Binding to Kindlin-2 Protein Pleckstrin Homology Domain in Regulating Integrin Activation

Prostaglandin E2 Promotes Integrin αVβ3-dependent Endothelial Cell Adhesion, Rac-activation, and Spreading through cAMP/PKA-dependent Signaling

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