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Tyrosine phosphorylation-dependence of caveolae-mediated endocytosis.

Sverdlov M, Shajahan AN, Minshall RD - J. Cell. Mol. Med. (2007 Nov-Dec)

Bottom Line: Entrapment of cargo within caveolae induces activation of signalling cascades leading to caveolae fission and internalization.Activation of Src tyrosine kinase is an early and essential step that triggers detachment of loaded caveolae from the plasma membrane.In this review, we examine how Src-mediated phosphorylation regulates caveolae-mediated transport by orchestrating the localization and activity of essential proteins of the endocytic machinery to regulate caveolae formation and fission.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, College of Medicine at Chicago, Chicago, IL 60612, USA.

ABSTRACT
Caveolae are flask-shaped plasma membrane invaginations that mediate endocytosis and transcytosis of plasma macromolecules, such as albumin, insulin and low-density lipoprotein (LDL), as well as certain viruses, bacteria and bacterial toxins. Caveolae-mediated transcytosis of macromolecules is critical for maintaining vascular homeostasis by regulating the oncotic pressure gradient and tissue delivery of drugs, vitamins, lipids and ions. Entrapment of cargo within caveolae induces activation of signalling cascades leading to caveolae fission and internalization. Activation of Src tyrosine kinase is an early and essential step that triggers detachment of loaded caveolae from the plasma membrane. In this review, we examine how Src-mediated phosphorylation regulates caveolae-mediated transport by orchestrating the localization and activity of essential proteins of the endocytic machinery to regulate caveolae formation and fission.

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Src-dependent signalling of caveolae-mediated endocytosis. Caveolae are the primary vesicular transporters or ‘carriers’ in endothelial cells. Clustering of various receptors, for example albumin binding protein gp60, initiates endocytosis via caveolae by associating with caveolin-1 and activating Src-family tyrosine kinase signalling (A, B). Caveolin-1 plays a central role as it serves a scaffolding function for components of the signalling machinery responsible for endocytosis and also stabilizes caveolae at the membrane. Gi/βγ-linked Src-family kinase activation (via autophosphorylation of Src Y416) (B) in turn phosphorylates tyrosine residues on caveolin-1 (Y14) and caveolin-2 (Y19, Y27) (C), which may destabilize membrane-associated hetero-oligomers (C), and the GTPase dynamin-2 (Y231, Y597) which is thought to ‘pinch’ caveolae from the plasma membrane (D). Src-dependent phosphorylation is hypothesized to be the trigger that activates caveolar fission by decreasing the rigid structure of the caveolar coat and activating dynamin pinchase function.
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fig02: Src-dependent signalling of caveolae-mediated endocytosis. Caveolae are the primary vesicular transporters or ‘carriers’ in endothelial cells. Clustering of various receptors, for example albumin binding protein gp60, initiates endocytosis via caveolae by associating with caveolin-1 and activating Src-family tyrosine kinase signalling (A, B). Caveolin-1 plays a central role as it serves a scaffolding function for components of the signalling machinery responsible for endocytosis and also stabilizes caveolae at the membrane. Gi/βγ-linked Src-family kinase activation (via autophosphorylation of Src Y416) (B) in turn phosphorylates tyrosine residues on caveolin-1 (Y14) and caveolin-2 (Y19, Y27) (C), which may destabilize membrane-associated hetero-oligomers (C), and the GTPase dynamin-2 (Y231, Y597) which is thought to ‘pinch’ caveolae from the plasma membrane (D). Src-dependent phosphorylation is hypothesized to be the trigger that activates caveolar fission by decreasing the rigid structure of the caveolar coat and activating dynamin pinchase function.

Mentions: The mechanism by which receptor clustering in caveolae activates Src kinases is not completely understood. Activation of Src kinase and Src-mediated phosphorylation of caveolin-1, caveolin-2 and dynamin-2 represent early and essential steps in this cascade (Fig. 2). The phosphorylation state of these proteins may regulate their three-dimensional structure, activity, localization and set of binding partners. Therefore, the primary function of Src in caveolae-mediated endocytosis has been proposed to be the regulation and assembly of multi-protein complexes responsible for caveolae fission and internalization [10]. Treatment of bovine lung endothelial cells with pertussis toxin or a dominant negative Gαi construct encoding the carboxyl-terminal 11 amino acids of Gαi inhibited endocytosis of iodinated albumin and vesicle formation induced by gp60 cross-linking in endothelial cells, illustrating that caveolar internalization may be regulated by a Gi-linked pathway [10]. Also, both activation and inhibition of Gβγ had a profound effect on Src activation and caveolae-mediated endocytosis of cholera toxin subunit B and albumin [40], suggesting that heterotrimeric G-protein Gi is upstream of Src in the signalling cascade initiated by albumin which is then internalized and transported in caveolae.


Tyrosine phosphorylation-dependence of caveolae-mediated endocytosis.

Sverdlov M, Shajahan AN, Minshall RD - J. Cell. Mol. Med. (2007 Nov-Dec)

Src-dependent signalling of caveolae-mediated endocytosis. Caveolae are the primary vesicular transporters or ‘carriers’ in endothelial cells. Clustering of various receptors, for example albumin binding protein gp60, initiates endocytosis via caveolae by associating with caveolin-1 and activating Src-family tyrosine kinase signalling (A, B). Caveolin-1 plays a central role as it serves a scaffolding function for components of the signalling machinery responsible for endocytosis and also stabilizes caveolae at the membrane. Gi/βγ-linked Src-family kinase activation (via autophosphorylation of Src Y416) (B) in turn phosphorylates tyrosine residues on caveolin-1 (Y14) and caveolin-2 (Y19, Y27) (C), which may destabilize membrane-associated hetero-oligomers (C), and the GTPase dynamin-2 (Y231, Y597) which is thought to ‘pinch’ caveolae from the plasma membrane (D). Src-dependent phosphorylation is hypothesized to be the trigger that activates caveolar fission by decreasing the rigid structure of the caveolar coat and activating dynamin pinchase function.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401290&req=5

fig02: Src-dependent signalling of caveolae-mediated endocytosis. Caveolae are the primary vesicular transporters or ‘carriers’ in endothelial cells. Clustering of various receptors, for example albumin binding protein gp60, initiates endocytosis via caveolae by associating with caveolin-1 and activating Src-family tyrosine kinase signalling (A, B). Caveolin-1 plays a central role as it serves a scaffolding function for components of the signalling machinery responsible for endocytosis and also stabilizes caveolae at the membrane. Gi/βγ-linked Src-family kinase activation (via autophosphorylation of Src Y416) (B) in turn phosphorylates tyrosine residues on caveolin-1 (Y14) and caveolin-2 (Y19, Y27) (C), which may destabilize membrane-associated hetero-oligomers (C), and the GTPase dynamin-2 (Y231, Y597) which is thought to ‘pinch’ caveolae from the plasma membrane (D). Src-dependent phosphorylation is hypothesized to be the trigger that activates caveolar fission by decreasing the rigid structure of the caveolar coat and activating dynamin pinchase function.
Mentions: The mechanism by which receptor clustering in caveolae activates Src kinases is not completely understood. Activation of Src kinase and Src-mediated phosphorylation of caveolin-1, caveolin-2 and dynamin-2 represent early and essential steps in this cascade (Fig. 2). The phosphorylation state of these proteins may regulate their three-dimensional structure, activity, localization and set of binding partners. Therefore, the primary function of Src in caveolae-mediated endocytosis has been proposed to be the regulation and assembly of multi-protein complexes responsible for caveolae fission and internalization [10]. Treatment of bovine lung endothelial cells with pertussis toxin or a dominant negative Gαi construct encoding the carboxyl-terminal 11 amino acids of Gαi inhibited endocytosis of iodinated albumin and vesicle formation induced by gp60 cross-linking in endothelial cells, illustrating that caveolar internalization may be regulated by a Gi-linked pathway [10]. Also, both activation and inhibition of Gβγ had a profound effect on Src activation and caveolae-mediated endocytosis of cholera toxin subunit B and albumin [40], suggesting that heterotrimeric G-protein Gi is upstream of Src in the signalling cascade initiated by albumin which is then internalized and transported in caveolae.

Bottom Line: Entrapment of cargo within caveolae induces activation of signalling cascades leading to caveolae fission and internalization.Activation of Src tyrosine kinase is an early and essential step that triggers detachment of loaded caveolae from the plasma membrane.In this review, we examine how Src-mediated phosphorylation regulates caveolae-mediated transport by orchestrating the localization and activity of essential proteins of the endocytic machinery to regulate caveolae formation and fission.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, College of Medicine at Chicago, Chicago, IL 60612, USA.

ABSTRACT
Caveolae are flask-shaped plasma membrane invaginations that mediate endocytosis and transcytosis of plasma macromolecules, such as albumin, insulin and low-density lipoprotein (LDL), as well as certain viruses, bacteria and bacterial toxins. Caveolae-mediated transcytosis of macromolecules is critical for maintaining vascular homeostasis by regulating the oncotic pressure gradient and tissue delivery of drugs, vitamins, lipids and ions. Entrapment of cargo within caveolae induces activation of signalling cascades leading to caveolae fission and internalization. Activation of Src tyrosine kinase is an early and essential step that triggers detachment of loaded caveolae from the plasma membrane. In this review, we examine how Src-mediated phosphorylation regulates caveolae-mediated transport by orchestrating the localization and activity of essential proteins of the endocytic machinery to regulate caveolae formation and fission.

Show MeSH
Related in: MedlinePlus