Tyrosine phosphorylation-dependence of caveolae-mediated endocytosis

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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 Srcmediated 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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Regulated portals of entry into the cell.

Sean D. Conner, Sandra Schmid (2003)

The plasma membrane is the interface between cells and their harsh environment. Uptake of nutrients and all communication among cells and between cells and their environment occurs through this interface. 'Endocytosis' encompasses several diverse mechanisms by which cells internalize macromolecules and particles into transport vesicles derived from the plasma membrane. It controls entry into the cell and has a crucial role in development, the immune response, neurotransmission, intercellular communication, signal transduction, and cellular and organismal homeostasis. As the complexity of molecular interactions governing endocytosis are revealed, it has become increasingly clear that it is tightly coordinated and coupled with overall cell physiology and thus, must be viewed in a broader context than simple vesicular trafficking.

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Caveolin, a protein component of caveolae membrane coats.

K. Rothberg, J Heuser, W C Donzell … (1992)

Caveolae have been implicated in the transcytosis of macromolecules across endothelial cells and in the receptor-mediated uptake of 5-methyltetrahydrofolate. Structural studies indicate that caveolae are decorated on their cytoplasmic surface by a unique array of filaments or strands that form striated coatings. To understand how these nonclathrin-coated pits function, we performed structural analysis of the striated coat and searched for the molecular component(s) of the coat material. The coat cannot be removed by washing with high salt; however, exposure of membranes to cholesterol-binding drugs caused invaginated caveolae to flatten and the striated coat to disassemble. Antibodies directed against a 22 kd substrate for v-src tyrosine kinase in virus-transformed chick embryo fibroblasts decorated the filaments, suggesting that this molecule is a component of the coat. We have named the molecule caveolin. Caveolae represent a third type of coated membrane specialization that is involved in molecular transport.

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Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities.

B Razani, J A Engelman, X. -B. Wang … (2001)

Caveolin-1 is the principal structural protein of caveolae membranes in fibroblasts and endothelia. Recently, we have shown that the human CAV-1 gene is localized to a suspected tumor suppressor locus, and mutations in Cav-1 have been implicated in human cancer. Here, we created a caveolin-1 null (CAV-1 -/-) mouse model, using standard homologous recombination techniques, to assess the role of caveolin-1 in caveolae biogenesis, endocytosis, cell proliferation, and endothelial nitric-oxide synthase (eNOS) signaling. Surprisingly, Cav-1 null mice are viable. We show that these mice lack caveolin-1 protein expression and plasmalemmal caveolae. In addition, analysis of cultured fibroblasts from Cav-1 null embryos reveals the following: (i) a loss of caveolin-2 protein expression; (ii) defects in the endocytosis of a known caveolar ligand, i.e. fluorescein isothiocyanate-albumin; and (iii) a hyperproliferative phenotype. Importantly, these phenotypic changes are reversed by recombinant expression of the caveolin-1 cDNA. Furthermore, examination of the lung parenchyma (an endothelial-rich tissue) shows hypercellularity with thickened alveolar septa and an increase in the number of vascular endothelial growth factor receptor (Flk-1)-positive endothelial cells. As predicted, endothelial cells from Cav-1 null mice lack caveolae membranes. Finally, we examined eNOS signaling by measuring the physiological response of aortic rings to various stimuli. Our results indicate that eNOS activity is up-regulated in Cav-1 null animals, and this activity can be blunted by using a specific NOS inhibitor, nitro-l-arginine methyl ester. These findings are in accordance with previous in vitro studies showing that caveolin-1 is an endogenous inhibitor of eNOS. Thus, caveolin-1 expression is required to stabilize the caveolin-2 protein product, to mediate the caveolar endocytosis of specific ligands, to negatively regulate the proliferation of certain cell types, and to provide tonic inhibition of eNOS activity in endothelial cells.

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Author and article information

Journal

Journal ID (nlm-ta): J Cell Mol Med

Journal ID (iso-abbrev): J. Cell. Mol. Med

Journal ID (publisher-id): jcmm

Title: Journal of Cellular and Molecular Medicine

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 1582-1838

ISSN (Electronic): 1582-4934

Publication date (Print): November 2007

Publication date (Electronic): 26 September 2007

Volume: 11

Issue: 6

Pages: 1239-1250

Affiliations

[a ]Departments of Pharmacology and Anesthesiology, Center for Lung and Vascular Biology, University of Illinois, College of Medicine at Chicago, Chicago, IL, USA

[b ]Lombardi Comprehensive Cancer Centre, Georgetown University, Washington DC, USA

Author notes

*Correspondence to: Richard D. MINSHALL, Department of Pharmacology, 835 S. Wolcott Avenue (m/c 868), Chicago, IL 60612, USA. Tel.: +31 (2) 99 6-16 55; Fax: +31 (2) 99 6-12 25 E-mail: rminsh@ 123456uic.edu

Guest Editor: R. V. Stan

Article

DOI: 10.1111/j.1582-4934.2007.00127.x

PMC ID: 4401290

PubMed ID: 18205698

SO-VID: c3454ed9-fc88-4d2f-a584-9a9599eaf93b

History

Date received : 16 July 2007

Date accepted : 20 September 2007

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Tyrosine phosphorylation-dependence of caveolae-mediated endocytosis

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Most cited references 90

Regulated portals of entry into the cell.

Caveolin, a protein component of caveolae membrane coats.

Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities.

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Cited by 31

Most referenced authors 1,952