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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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Phosphorylation map of the caveolin family of proteins. Caveolins are highly homologous and conserved proteins. All isoforms contain membrane-spanning, oligomerization and caveolin-scaffolding domains. (A) Caveolin-1α isoform consists of 178 amino acids with phosphorylation sites at tyrosine 14 and serine 80. Caveolin-1β isoform lacks the first 31 amino acids, and thus it does not contain the tyrosine phosphorylation site. Residues 75–158 (part of scaffolding domain, membrane- spanning domain, and most of the C-terminus) are involved in binding Dynamin 2. Scaffolding and membrane-spanning domains of caveolin-1 also participate in homo-oligomerization and formation of heteroligomers with caveolin-2. (B) Caveolin-2 is ∼50% homologues to caveolin-1 and caveolin-2α isoform contains 162 amino acids with phosphorylation sites at tyrosines 19 and 27, and serines 23 and 36. Caveolin-2β isoform, produced by alternative splicing of mRNA, is truncated by 13 N-terminal amino acids, while no information is yet available about the phosphorylation of the caveolin-2α isoform. (C) Caveolin-3 is a muscle-specific isoform, which contains 151 amino acids and is very homologous to caveolin-1. No phosphorylation sites have been demonstrated for caveolin-3 to date.
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fig01: Phosphorylation map of the caveolin family of proteins. Caveolins are highly homologous and conserved proteins. All isoforms contain membrane-spanning, oligomerization and caveolin-scaffolding domains. (A) Caveolin-1α isoform consists of 178 amino acids with phosphorylation sites at tyrosine 14 and serine 80. Caveolin-1β isoform lacks the first 31 amino acids, and thus it does not contain the tyrosine phosphorylation site. Residues 75–158 (part of scaffolding domain, membrane- spanning domain, and most of the C-terminus) are involved in binding Dynamin 2. Scaffolding and membrane-spanning domains of caveolin-1 also participate in homo-oligomerization and formation of heteroligomers with caveolin-2. (B) Caveolin-2 is ∼50% homologues to caveolin-1 and caveolin-2α isoform contains 162 amino acids with phosphorylation sites at tyrosines 19 and 27, and serines 23 and 36. Caveolin-2β isoform, produced by alternative splicing of mRNA, is truncated by 13 N-terminal amino acids, while no information is yet available about the phosphorylation of the caveolin-2α isoform. (C) Caveolin-3 is a muscle-specific isoform, which contains 151 amino acids and is very homologous to caveolin-1. No phosphorylation sites have been demonstrated for caveolin-3 to date.

Mentions: The main structural unit and biological marker of caveolae is the 20–22 kD integral membrane protein, caveolin. To date, several different caveolin iso-forms have been identified: caveolin-1α, caveolin-1β, caveolin-2α, caveolin-2β, caveolin-2γ and caveolin-3 [13] (Fig. 1). Caveolin-1 and -2 are ubiquitously expressed, while caveolin-3 is confined to muscle cells [14–16]. The α and β isoforms of caveolin-1 result from alternative splicing from a single gene; the β form is 32 amino acids shorter than the α form [14]. Caveolin-1 is required for the biogenesis of non-muscle caveolae since the overexpression of caveolin- 1 in cells that lack endogenous caveolin-1 results in the de novo formation of caveolae [17, 18]. In cells that loose caveolin-1 expression during transformation, caveolae are no longer present [19]. Moreover, endothelium and adipose tissue of mice defective in caveolin-1 are devoid of caveolae [20–24]. Suppression of caveolin-1 expression by siRNA leads to a dramatic decrease in the number of caveolae in endothelial cells, which returns to normal following recovery of caveolin-1 expression [25].


Tyrosine phosphorylation-dependence of caveolae-mediated endocytosis.

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

Phosphorylation map of the caveolin family of proteins. Caveolins are highly homologous and conserved proteins. All isoforms contain membrane-spanning, oligomerization and caveolin-scaffolding domains. (A) Caveolin-1α isoform consists of 178 amino acids with phosphorylation sites at tyrosine 14 and serine 80. Caveolin-1β isoform lacks the first 31 amino acids, and thus it does not contain the tyrosine phosphorylation site. Residues 75–158 (part of scaffolding domain, membrane- spanning domain, and most of the C-terminus) are involved in binding Dynamin 2. Scaffolding and membrane-spanning domains of caveolin-1 also participate in homo-oligomerization and formation of heteroligomers with caveolin-2. (B) Caveolin-2 is ∼50% homologues to caveolin-1 and caveolin-2α isoform contains 162 amino acids with phosphorylation sites at tyrosines 19 and 27, and serines 23 and 36. Caveolin-2β isoform, produced by alternative splicing of mRNA, is truncated by 13 N-terminal amino acids, while no information is yet available about the phosphorylation of the caveolin-2α isoform. (C) Caveolin-3 is a muscle-specific isoform, which contains 151 amino acids and is very homologous to caveolin-1. No phosphorylation sites have been demonstrated for caveolin-3 to date.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4401290&req=5

fig01: Phosphorylation map of the caveolin family of proteins. Caveolins are highly homologous and conserved proteins. All isoforms contain membrane-spanning, oligomerization and caveolin-scaffolding domains. (A) Caveolin-1α isoform consists of 178 amino acids with phosphorylation sites at tyrosine 14 and serine 80. Caveolin-1β isoform lacks the first 31 amino acids, and thus it does not contain the tyrosine phosphorylation site. Residues 75–158 (part of scaffolding domain, membrane- spanning domain, and most of the C-terminus) are involved in binding Dynamin 2. Scaffolding and membrane-spanning domains of caveolin-1 also participate in homo-oligomerization and formation of heteroligomers with caveolin-2. (B) Caveolin-2 is ∼50% homologues to caveolin-1 and caveolin-2α isoform contains 162 amino acids with phosphorylation sites at tyrosines 19 and 27, and serines 23 and 36. Caveolin-2β isoform, produced by alternative splicing of mRNA, is truncated by 13 N-terminal amino acids, while no information is yet available about the phosphorylation of the caveolin-2α isoform. (C) Caveolin-3 is a muscle-specific isoform, which contains 151 amino acids and is very homologous to caveolin-1. No phosphorylation sites have been demonstrated for caveolin-3 to date.
Mentions: The main structural unit and biological marker of caveolae is the 20–22 kD integral membrane protein, caveolin. To date, several different caveolin iso-forms have been identified: caveolin-1α, caveolin-1β, caveolin-2α, caveolin-2β, caveolin-2γ and caveolin-3 [13] (Fig. 1). Caveolin-1 and -2 are ubiquitously expressed, while caveolin-3 is confined to muscle cells [14–16]. The α and β isoforms of caveolin-1 result from alternative splicing from a single gene; the β form is 32 amino acids shorter than the α form [14]. Caveolin-1 is required for the biogenesis of non-muscle caveolae since the overexpression of caveolin- 1 in cells that lack endogenous caveolin-1 results in the de novo formation of caveolae [17, 18]. In cells that loose caveolin-1 expression during transformation, caveolae are no longer present [19]. Moreover, endothelium and adipose tissue of mice defective in caveolin-1 are devoid of caveolae [20–24]. Suppression of caveolin-1 expression by siRNA leads to a dramatic decrease in the number of caveolae in endothelial cells, which returns to normal following recovery of caveolin-1 expression [25].

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