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Integrin regulation of caveolin function.

Salanueva IJ, Cerezo A, Guadamillas MC, del Pozo MA - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: Caveolae are unique organelles that are found in the plasma membrane of many cell types.Caveolin-1, a constitutive protein of caveolae, has been implicated in the regulation of cell growth, lipid trafficking, endocytosis and cell migration.Phosphorylation of caveolin-1 on Tyr 14 is involved in integrin-regulated caveolae trafficking and also in signalling at focal adhesions in migrating cells.

View Article: PubMed Central - PubMed

Affiliation: Integrin Signaling Laboratory, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.

ABSTRACT
Caveolae are unique organelles that are found in the plasma membrane of many cell types. They participate in various processes such as lipid recycling, cellular signalling and endocytosis. A variety of signalling molecules localize to caveolae in response to various stimuli, providing a potential mechanism for the spatial regulation of signal transduction pathways. Caveolin-1, a constitutive protein of caveolae, has been implicated in the regulation of cell growth, lipid trafficking, endocytosis and cell migration. Phosphorylation of caveolin-1 on Tyr 14 is involved in integrin-regulated caveolae trafficking and also in signalling at focal adhesions in migrating cells. In this review, we focus on recent studies that describe the role of caveolin-1 in integrin signal transduction, and how this interplay links extracellular matrix anchorage to cell proliferation, polarity and directional migration.

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Related in: MedlinePlus

Dual role of Cav-1 Y14 phosphorylation: phosphorylat-ed caveolin (pYCav-1) is involved in the control of integrin-mediated signal transduction and caveolae-mediated cholesterol-enriched membrane microdomains (CEMM) endocy-tosis. In adherent cells (A), pYCav-1 is retained mainly at focal adhesions and its concentration at caveolae is low. In focal adhesions (FA), pYCav-1 is involved in controlling cell polarity and directional migration. We propose a model in which pYCav-1 regulates Src activity by recruiting C–terminal Src kinase (Csk) to FA; Csk inhibits Src by phosphorylation and this modulates Src-dependent inactivation of Rho through p190RhoGAP. Moreover, integrin activation targets Rac and other proteins to caveolae/CEMMs, allowing interaction with effector molecules. In the case of Rac, integrins increase the affinity for Rac by modulating CEMMs, thus displacing Rac from its cytosolic ligand, Rho-GDI (magnification in A). This process may be controlled directly by integrins or by an unknown pathway that regulates the localization of pYCav-1 at focal adhesions, preventing CEMM internalization. The presence of CEMMs in the plasma membrane allows the activation of multiple signalling pathways. When integrin signalling is interrupted, as in suspended cells or at areas of the cell that transiently detach from the substrate (B), CEMMs are endocytosed by a mechanism involving pYCav-1 translocation to caveolae. This process uncouples many signalling intermediates from their effectors, thereby shutting down associated signalling pathways.
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fig01: Dual role of Cav-1 Y14 phosphorylation: phosphorylat-ed caveolin (pYCav-1) is involved in the control of integrin-mediated signal transduction and caveolae-mediated cholesterol-enriched membrane microdomains (CEMM) endocy-tosis. In adherent cells (A), pYCav-1 is retained mainly at focal adhesions and its concentration at caveolae is low. In focal adhesions (FA), pYCav-1 is involved in controlling cell polarity and directional migration. We propose a model in which pYCav-1 regulates Src activity by recruiting C–terminal Src kinase (Csk) to FA; Csk inhibits Src by phosphorylation and this modulates Src-dependent inactivation of Rho through p190RhoGAP. Moreover, integrin activation targets Rac and other proteins to caveolae/CEMMs, allowing interaction with effector molecules. In the case of Rac, integrins increase the affinity for Rac by modulating CEMMs, thus displacing Rac from its cytosolic ligand, Rho-GDI (magnification in A). This process may be controlled directly by integrins or by an unknown pathway that regulates the localization of pYCav-1 at focal adhesions, preventing CEMM internalization. The presence of CEMMs in the plasma membrane allows the activation of multiple signalling pathways. When integrin signalling is interrupted, as in suspended cells or at areas of the cell that transiently detach from the substrate (B), CEMMs are endocytosed by a mechanism involving pYCav-1 translocation to caveolae. This process uncouples many signalling intermediates from their effectors, thereby shutting down associated signalling pathways.

Mentions: An alternative, indirect mechanism of signalling regulation by caveolin and caveolae arises from their role in cholesterol/CEMM trafficking. CEMMs arise by the preferential clustering of sphingolipids and cholesterol into moving platforms, or lipid rafts, and it has been proposed that some proteins selectively bind to these rafts while others are excluded [1, 44]. In this way, receptors that become activated upon lig- and binding can be concentrated in close proximity to their effector molecules in membrane microdomains from which potential inhibitors, such as membrane phosphatases would be excluded. This is represented in Figure 1A. Supporting this idea, specific phos-photyrosine-kinase activities are known to concentrate at lipid rafts [45], what seems to be an effective mechanism for modulating cross-talk among different pathways. By regulating the trafficking of lipid domains, caveolin could thus indirectly modulate signalling. Through these mechanisms, caveolae may serve as a matrix for early signal transduction events, and reorganization of these domains could critically determine the functional outcomes of signalling cascades.


Integrin regulation of caveolin function.

Salanueva IJ, Cerezo A, Guadamillas MC, del Pozo MA - J. Cell. Mol. Med. (2007 Sep-Oct)

Dual role of Cav-1 Y14 phosphorylation: phosphorylat-ed caveolin (pYCav-1) is involved in the control of integrin-mediated signal transduction and caveolae-mediated cholesterol-enriched membrane microdomains (CEMM) endocy-tosis. In adherent cells (A), pYCav-1 is retained mainly at focal adhesions and its concentration at caveolae is low. In focal adhesions (FA), pYCav-1 is involved in controlling cell polarity and directional migration. We propose a model in which pYCav-1 regulates Src activity by recruiting C–terminal Src kinase (Csk) to FA; Csk inhibits Src by phosphorylation and this modulates Src-dependent inactivation of Rho through p190RhoGAP. Moreover, integrin activation targets Rac and other proteins to caveolae/CEMMs, allowing interaction with effector molecules. In the case of Rac, integrins increase the affinity for Rac by modulating CEMMs, thus displacing Rac from its cytosolic ligand, Rho-GDI (magnification in A). This process may be controlled directly by integrins or by an unknown pathway that regulates the localization of pYCav-1 at focal adhesions, preventing CEMM internalization. The presence of CEMMs in the plasma membrane allows the activation of multiple signalling pathways. When integrin signalling is interrupted, as in suspended cells or at areas of the cell that transiently detach from the substrate (B), CEMMs are endocytosed by a mechanism involving pYCav-1 translocation to caveolae. This process uncouples many signalling intermediates from their effectors, thereby shutting down associated signalling pathways.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401268&req=5

fig01: Dual role of Cav-1 Y14 phosphorylation: phosphorylat-ed caveolin (pYCav-1) is involved in the control of integrin-mediated signal transduction and caveolae-mediated cholesterol-enriched membrane microdomains (CEMM) endocy-tosis. In adherent cells (A), pYCav-1 is retained mainly at focal adhesions and its concentration at caveolae is low. In focal adhesions (FA), pYCav-1 is involved in controlling cell polarity and directional migration. We propose a model in which pYCav-1 regulates Src activity by recruiting C–terminal Src kinase (Csk) to FA; Csk inhibits Src by phosphorylation and this modulates Src-dependent inactivation of Rho through p190RhoGAP. Moreover, integrin activation targets Rac and other proteins to caveolae/CEMMs, allowing interaction with effector molecules. In the case of Rac, integrins increase the affinity for Rac by modulating CEMMs, thus displacing Rac from its cytosolic ligand, Rho-GDI (magnification in A). This process may be controlled directly by integrins or by an unknown pathway that regulates the localization of pYCav-1 at focal adhesions, preventing CEMM internalization. The presence of CEMMs in the plasma membrane allows the activation of multiple signalling pathways. When integrin signalling is interrupted, as in suspended cells or at areas of the cell that transiently detach from the substrate (B), CEMMs are endocytosed by a mechanism involving pYCav-1 translocation to caveolae. This process uncouples many signalling intermediates from their effectors, thereby shutting down associated signalling pathways.
Mentions: An alternative, indirect mechanism of signalling regulation by caveolin and caveolae arises from their role in cholesterol/CEMM trafficking. CEMMs arise by the preferential clustering of sphingolipids and cholesterol into moving platforms, or lipid rafts, and it has been proposed that some proteins selectively bind to these rafts while others are excluded [1, 44]. In this way, receptors that become activated upon lig- and binding can be concentrated in close proximity to their effector molecules in membrane microdomains from which potential inhibitors, such as membrane phosphatases would be excluded. This is represented in Figure 1A. Supporting this idea, specific phos-photyrosine-kinase activities are known to concentrate at lipid rafts [45], what seems to be an effective mechanism for modulating cross-talk among different pathways. By regulating the trafficking of lipid domains, caveolin could thus indirectly modulate signalling. Through these mechanisms, caveolae may serve as a matrix for early signal transduction events, and reorganization of these domains could critically determine the functional outcomes of signalling cascades.

Bottom Line: Caveolae are unique organelles that are found in the plasma membrane of many cell types.Caveolin-1, a constitutive protein of caveolae, has been implicated in the regulation of cell growth, lipid trafficking, endocytosis and cell migration.Phosphorylation of caveolin-1 on Tyr 14 is involved in integrin-regulated caveolae trafficking and also in signalling at focal adhesions in migrating cells.

View Article: PubMed Central - PubMed

Affiliation: Integrin Signaling Laboratory, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.

ABSTRACT
Caveolae are unique organelles that are found in the plasma membrane of many cell types. They participate in various processes such as lipid recycling, cellular signalling and endocytosis. A variety of signalling molecules localize to caveolae in response to various stimuli, providing a potential mechanism for the spatial regulation of signal transduction pathways. Caveolin-1, a constitutive protein of caveolae, has been implicated in the regulation of cell growth, lipid trafficking, endocytosis and cell migration. Phosphorylation of caveolin-1 on Tyr 14 is involved in integrin-regulated caveolae trafficking and also in signalling at focal adhesions in migrating cells. In this review, we focus on recent studies that describe the role of caveolin-1 in integrin signal transduction, and how this interplay links extracellular matrix anchorage to cell proliferation, polarity and directional migration.

Show MeSH
Related in: MedlinePlus