Organized Endothelial Cell Surface Signal Transduction in Caveolae Distinct from Glycosylphosphatidylinositol-anchored Protein Microdomains

Li, Jun; Oh, Phil; Horner, Thierry; Rogers, Rick A.; Schnitzer, Jan E.

doi:10.1074/jbc.272.11.7211

Cited by 259 publications

(226 citation statements)

References 53 publications

(104 reference statements)

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“…As dynamic vesicular carriers, they bud directly from the plasma membranes to form free transport vesicles containing the necessary molecular machinery for directed docking and fusion to mediate the endocytosis and transcytosis of select macromolecules (reviewed in Schnitzer, 1993;Schnitzer et al, 1994). They also have been implicated in signal transduction (Strosberg, 1991;Chang et al, 1994;Liu et al, 1997). Caveolin-1/VIP21, a 22 kD protein, appears to be an integral part of the striated coat of caveolae structures (Rothberg et al, 1992;Dupree et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells

et al. 1998

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Cancer development is a multistage process that results from the step-wise acquisition of somatic alterations in diverse genes. Recent studies indicate that caveolin-1 expression correlates with the level of oncogenic transformation in NIH3T3 cells, suggesting that caveolin in caveolae may regulate normal cell proliferation. In order to better understand potential functions of caveolin-1 in cancer development, we have studied expression levels of caveolin-1 in human breast cancer cells, and have found that caveolin expression is signi®cantly reduced in human breast cancer cells compared with their normal mammary epithelial counterparts. When the caveolin cDNA linked to the CMV promoter is transfected into human mammary cancer cells having no detectable endogenous caveolin, overexpression of caveolin-1 resulted in substantial growth inhibition, as seen by the 50% decrease in growth rate and by *l5-fold reduction in colony formation in soft agar. In addition, characterization of caveolin-1 expression during cell cycle progression indicates that expression of a-caveolin-1 is regulated during cell cycle. Furthermore p53-de®cient cells showed a loss in caveolin expression. In summary, the overall expression patterns, its ability to inhibit tumor growth in culture, its regulation during the cell cycle, and the loss of expression in p53-de®cient cells all are consistent with an important growth regulating function for caveolin-1 in normal human mammary cells, that needs to be repressed in oncogenic transformation and tumor cell growth.

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Section: Introductionmentioning

confidence: 99%

Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells

et al. 1998

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“…Purified caveolae membranes are dramatically enriched in caveolin-1 and -2 and have been shown to contain tyrosine kinase activity (11,14,22,25,33). A number of Src family tyrosine kinases (c-Src, c-Yes, Lyn, Fyn, Lck, and c-Fgr) and receptor tyrosine kinases (Ins-R, EGF-R, and PDGF-R) all copurify with caveolae (Refs.…”

Section: Purified Caveolae-enriched Membranes Contain a Kinase Activimentioning

confidence: 99%

Src-induced Phosphorylation of Caveolin-2 on Tyrosine 19

Lee

Park

Wang

et al. 2002

Journal of Biological Chemistry

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Caveolin-2 is the least well studied member of the caveolin gene family. It is believed that caveolin-2 is an "accessory protein" that functions in conjunction with caveolin-1. At the level of the ER, caveolin-2 interacts with caveolin-1 to form a high molecular mass heterooligomeric complex that is targeted to lipid rafts and drives the formation of caveolae. However, caveolin-2 is not required for caveolae formation, implying that it may fulfill some unknown regulatory role. Here, we present the first evidence that caveolin-2 is a phosphoprotein. We show that caveolin-2 undergoes Src-induced phosphorylation on tyrosine 19. To study this phosphorylation event in vivo, we generated a novel phospho-specific antibody probe that only recognizes phosphocaveolin-2 (Tyr(P) 19 ). We then used NIH-3T3 cells stably overexpressing c-Src to examine the localization and biochemical properties of phosphocaveolin-2 (Tyr(P) 19 ). Our results indicate that phosphocaveolin-2 (Tyr(P) 19 ) is localized near focal adhesions, remains associated with lipid rafts/caveolae, but no longer forms a high molecular mass hetero-oligomer with caveolin-1. Instead, phosphocaveolin-2 (Tyr(P) 19 ) behaves as a monomer/dimer in velocity gradients. Thus, we conclude that the tyrosine phosphorylation of caveolin-2 (Tyr(P) 19 ) may function as a signal that is recognized by the cellular machinery to induce the dissociation of caveolin-2 from caveolin-1 oligomers. We also demonstrate that (i) insulin-stimulation of adipocytes and (ii) integrin ligation of endothelial cells can both induce the tyrosine phosphorylation of caveolin-2 (Tyr(P) 19 ). During integrin ligation, phosphocaveolin-2 (Tyr(P) 19 ) co-localizes with activated FAK at focal adhesions. Thus, phosphocaveolin-2 (Tyr(P) 19 ) may function as a docking site for Src homology domain-2 (SH2) domain containing proteins during signal transduction. In support of this notion, we identify several SH2 domain containing proteins, namely c-Src, NCK, and Ras-GAP, that interact with caveolin-2 in a phosphorylation-dependent manner. Furthermore, our co-immunoprecipitation experiments show that caveolin-2 and Ras-GAP are constitutively associated in c-Src expressing NIH-3T3 cells, but not in untransfected NIH-3T3 cells.Receptor tyrosine kinases (RTKs) 1 contain one or more autophosphorylation sites. Upon ligand binding, a specific receptor is activated and undergoes autophosphorylation on specific tyrosine residues. One known function for tyrosine phosphorylation is to confer docking sites for Src homology domain-2 (SH2)-containing proteins. Numerous downstream signaling molecules possessing either intrinsic kinase activity or an adapter function are then recruited to the plasma membrane and utilize their SH2 domains to form hetero-oligomeric signaling complexes with activated RTKs.Numerous RTKs, such as epidermal growth factor receptor (EGF-R), platelet-derived growth factor receptor (PDGF-R), and insulin receptor (Ins-R), as well as non-receptor tyrosine kinases (NRTKs; Src-family tyrosine kinases) are ...

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“…Accordingly, Schnitzer and colleagues (143,180) have developed a protocol utilizing colloidal silica particles and polyacrylic acid treatment to separate caveolae from other Triton-insoluble microdomains including those on the cell surface, intracellular trans-Golgi networks, and exocytic/endocytic vesicles. This method permits isolation of plasma membranes of high purity.…”

Section: Lpp In Signaling Platformsmentioning

confidence: 99%

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

Nanjundan

Possmayer

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The lung contains two distinct forms of phosphatidic acid phosphatase (PAP). PAP1 is a cytosolic enzyme that is activated through fatty acid-induced translocation to the endoplasmic reticulum, where it converts phosphatidic acid (PA) to diacylglycerol (DAG) for the biosynthesis of phospholipids and neutral lipids. PAP1 is Mg2+ dependent and sulfhydryl reagent sensitive. PAP2 is a six-transmembrane-domain integral protein localized to the plasma membrane. Because PAP2 degrades sphingosine-1-phosphate (S1P) and ceramide-1-phosphate in addition to PA and lyso-PA, it has been renamed lipid phosphate phosphohydrolase (LPP). LPP is Mg2+independent and sulfhydryl reagent insensitive. This review describes LPP isoforms found in the lung and their location in signaling platforms (rafts/caveolae). Pulmonary LPPs likely function in the phospholipase D pathway, thereby controlling surfactant secretion. Through lowering the levels of lyso-PA and S1P, which serve as agonists for endothelial differentiation gene receptors, LPPs regulate cell division, differentiation, apoptosis, and mobility. LPP activity could also influence transdifferentiation of alveolar type II to type I cells. It is considered likely that these lipid phosphohydrolases have critical roles in lung morphogenesis and in acute lung injury and repair.

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Organized Endothelial Cell Surface Signal Transduction in Caveolae Distinct from Glycosylphosphatidylinositol-anchored Protein Microdomains

Cited by 259 publications

References 53 publications

Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells

Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells

Src-induced Phosphorylation of Caveolin-2 on Tyrosine 19

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

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