Counteracting Signaling Activities in Lipid Rafts Associated with the Invasion of Lung Epithelial Cells by Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa has the capacity to invade lung epithelial cells by co-opting the intrinsic endocytic properties of lipid rafts, which are rich in cholesterol, sphingolipids, and proteins, such as caveolin-1 and -2. We compared intratracheal Pseudomonas infection in wild type and caveolin-deficient mice to investigate the role of caveolin proteins in the pathogenesis of Pseudomonas pneumonia. Unlike wild type mice, which succumb to pneumonia, caveolin-deficient mice are resistant to Pseudomonas. We observed that Pseudomonas invasion of lung epithelial cells is dependent on caveolin-2 but not caveolin-1. Phosphorylation of caveolin-2 by Src family kinases is an essential event for Pseudomonas invasion. Our studies also reveal the existence of a distinct signaling mechanism in lung epithelial cells mediated by COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas invasion. Csk migrates to lipid raft domains, where it decreases phosphorylation of caveolin-2 by inactivating c-Src. Whereas Pseudomonas co-opts the endocytic properties of caveolin-2 for invasion, there also exists in these cells an intrinsic Csk-dependent cellular defense mechanism aimed at impairing this activity. The success of Pseudomonas in co-opting lipid raft-mediated endocytosis to invade lung epithelial cells may depend on the relative strengths of these counteracting signaling activities. Pseudomonas aeruginosa has the capacity to invade lung epithelial cells by co-opting the intrinsic endocytic properties of lipid rafts, which are rich in cholesterol, sphingolipids, and proteins, such as caveolin-1 and -2. We compared intratracheal Pseudomonas infection in wild type and caveolin-deficient mice to investigate the role of caveolin proteins in the pathogenesis of Pseudomonas pneumonia. Unlike wild type mice, which succumb to pneumonia, caveolin-deficient mice are resistant to Pseudomonas. We observed that Pseudomonas invasion of lung epithelial cells is dependent on caveolin-2 but not caveolin-1. Phosphorylation of caveolin-2 by Src family kinases is an essential event for Pseudomonas invasion. Our studies also reveal the existence of a distinct signaling mechanism in lung epithelial cells mediated by COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas invasion. Csk migrates to lipid raft domains, where it decreases phosphorylation of caveolin-2 by inactivating c-Src. Whereas Pseudomonas co-opts the endocytic properties of caveolin-2 for invasion, there also exists in these cells an intrinsic Csk-dependent cellular defense mechanism aimed at impairing this activity. The success of Pseudomonas in co-opting lipid raft-mediated endocytosis to invade lung epithelial cells may depend on the relative strengths of these counteracting signaling activities. Pseudomonas (Pa) 2The abbreviations used are: Pa, Pseudomonas; LEC, lung epithelial cell; cav, caveolin; Csk, COOH-terminal Src kinase; MCD, methyl-β-cyclodextrin; MLE-12, murine lung epithelial cell line-12; GFP, green fluorescent protein; cfu, colony-forming unit; BAL, bronchoalveolar lavage; PBS, phosphate-buffered saline. is an important cause of hospital-acquired and healthcare-associated pneumonia (1Fagon J.Y. Chastre J. Domart Y. Trouillet J.L. Gibert C. Clin. Infect. Dis. 1996; 23: 538-542Crossref PubMed Scopus (159) Google Scholar, 2Dunn M. Wunderink R.G. Clin. Chest Med. 1995; 16: 95-109PubMed Google Scholar, 3Driscoll J.A. Brody S.L. Kollef M.H. Drugs. 2007; 67: 351-368Crossref PubMed Scopus (576) Google Scholar, 4Crouch Brewer S. Wunderink R.G. Jones C.B. Leeper Jr., K.V. Chest. 1996; 109: 1019-1029Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Despite appropriate antibiotic therapy, the morbidity and mortality associated with Pa pneumonia remains high, at least partly due to the ability of Pa to resist antibiotic-mediated killing (1Fagon J.Y. Chastre J. Domart Y. Trouillet J.L. Gibert C. Clin. Infect. Dis. 1996; 23: 538-542Crossref PubMed Scopus (159) Google Scholar, 5Chastre J. Fagon J.Y. Am. J. Respir. Crit. Care Med. 2002; 165: 867-903Crossref PubMed Scopus (2129) Google Scholar). It has recently been recognized that Pa is not solely an extracellular pathogen and that Pa can invade lung epithelial cells (LECs) via lipid raft-mediated endocytosis (6Zaas D.W. Duncan M.J. Li G. Wright J.R. Abraham S.N. J. Biol. Chem. 2005; 280: 4864-4872Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 7Grassme H. Jendrossek V. Riehle A. von Kurthy G. Berger J. Schwarz H. Weller M. Kolesnick R. Gulbins E. Nat. Med. 2003; 9: 322-330Crossref PubMed Scopus (457) Google Scholar, 8Garcia-Medina R. Dunne W.M. Singh P.K. Brody S.L. Infect. Immun. 2005; 73: 8298-8305Crossref PubMed Scopus (93) Google Scholar). Lipid rafts are specialized areas of the plasma membrane that are detergent-insoluble, low density membrane fractions enriched in cholesterol and sphingolipids (9Anderson R.G. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1711) Google Scholar). An increasing number of pathogens have been recognized to co-opt the mechanism of lipid raft-mediated endocytosis in order to invade host cells (10Zaas D.W. Duncan M. Rae Wright J. Abraham S.N. Biochim. Biophys. Acta. 2005; 1746: 305-313Crossref PubMed Scopus (93) Google Scholar, 11Shin J.S. Abraham S.N. Microbes Infect. 2001; 3: 755-761Crossref PubMed Scopus (109) Google Scholar, 12Parton R.G. Richards A.A. Traffic. 2003; 4: 724-738Crossref PubMed Scopus (483) Google Scholar). We have previously shown that Pa co-opts the host endocytic machinery to invade both LECs where it can survive and replicate (6Zaas D.W. Duncan M.J. Li G. Wright J.R. Abraham S.N. J. Biol. Chem. 2005; 280: 4864-4872Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). The uptake of Pa requires the expression of several lipid raft-associated proteins, including the caveolin proteins (6Zaas D.W. Duncan M.J. Li G. Wright J.R. Abraham S.N. J. Biol. Chem. 2005; 280: 4864-4872Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Caveolin-1 and -2 are co-expressed on a wide range of cell types but are particularly abundant in endothelial cells, airway epithelial cells, and type I pneumocytes (9Anderson R.G. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1711) Google Scholar, 13Parolini I. Sargiacomo M. Galbiati F. Rizzo G. Grignani F. Engelman J.A. Okamoto T. Ikezu T. Scherer P.E. Mora R. Rodriguez-Boulan E. Peschle C. Lisanti M.P. J. Biol. Chem. 1999; 274: 25718-25725Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 14Mora R. Bonilha V.L. Marmorstein A. Scherer P.E. Brown D. Lisanti M.P. Rodriguez-Boulan E. J. Biol. Chem. 1999; 274: 25708-25717Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). Caveolin-1 has been implicated as a scaffolding protein for organizing and concentrating caveolin-interacting signaling molecules within caveolae. Caveolin-2 is the most divergent of the caveolin gene family, with only ∼50% similarity to caveolin-1 (15Scherer P.E. Okamoto T. Chun M. Nishimoto I. Lodish H.F. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 131-135Crossref PubMed Scopus (486) Google Scholar). Caveolin-2 interacts with caveolin-1 to form a hetero-oligomeric complex within lipid rafts (14Mora R. Bonilha V.L. Marmorstein A. Scherer P.E. Brown D. Lisanti M.P. Rodriguez-Boulan E. J. Biol. Chem. 1999; 274: 25708-25717Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). In order for caveolin-2 to be expressed, caveolin-1 serves as a chaperone to transport caveolin-2 to the plasma membrane. In the absence of caveolin-1, caveolin-2 is degraded in the Golgi apparatus, and no significant caveolin-2 is expressed (14Mora R. Bonilha V.L. Marmorstein A. Scherer P.E. Brown D. Lisanti M.P. Rodriguez-Boulan E. J. Biol. Chem. 1999; 274: 25708-25717Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). As expected based on these observations, the caveolin-1 knock-out mouse lacks expression of both caveolin-1 and -2 and is functionally deficient in both caveolin-1 and -2 (16Razani B. Engelman J.A. Wang X.B. Schubert W. Zhang X.L. Marks C.B. Macaluso F. Russell R.G. Li M. Pestell R.G. Di Vizio D. Hou Jr., H. Kneitz B. Lagaud G. Christ G.J. Edelmann W. Lisanti M.P. J. Biol. Chem. 2001; 276: 38121-38138Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). In addition to serving as key structural proteins that organize caveolae platforms, caveolin proteins are important in regulating endocytosis and cell signaling (17Williams T.M. Lisanti M.P. Ann. Med. 2004; 36: 584-595Crossref PubMed Scopus (304) Google Scholar, 18Schlegel A. Lisanti M.P. Cytokine Growth Factor Rev. 2001; 12: 41-51Crossref PubMed Scopus (70) Google Scholar). Caveolin proteins serve to regulate cell signaling pathways that are concentrated within lipid rafts and have recognized sites of tyrosine phosphorylation that interact with members of the Src family kinases (19Wang X.B. Lee H. Capozza F. Marmon S. Sotgia F. Brooks J.W. Campos-Gonzalez R. Lisanti M.P. Biochemistry. 2004; 43: 13694-13706Crossref PubMed Scopus (21) Google Scholar, 20Lee H. Volonte D. Galbiati F. Iyengar Campos-Gonzalez R. B. Pestell R.G. Scherer P.E. Lisanti M.P. PubMed Google Scholar, H. Wang X.B. Scherer P.E. P.E. Lisanti M.P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Wang A. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). of the caveolin knock-out mouse have shown that caveolin important within the lung (16Razani B. Engelman J.A. Wang X.B. Schubert W. Zhang X.L. Marks C.B. Macaluso F. Russell R.G. Li M. Pestell R.G. Di Vizio D. Hou Jr., H. Kneitz B. Lagaud G. Christ G.J. Edelmann W. Lisanti M.P. J. Biol. Chem. 2001; 276: 38121-38138Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, Zhang Y. F. E. J. Med. PubMed Scopus Google Scholar, B. Wang X.B. Engelman J.A. M. Lagaud G. Zhang X.L. Kneitz B. Hou Jr., H. Christ G.J. Edelmann W. Lisanti M.P. Biol. 2002; PubMed Scopus Google the role of caveolin proteins and lipid raft-mediated uptake in the pathogenesis of Pa pneumonia is not The of this is to investigate the role of caveolin proteins in the pathogenesis of Pa pneumonia. We have that Pa invasion of LECs is an important for Pa in the pathogenesis of pneumonia. The ability of Pa to invade LECs for a where Pa may be to replicate and host defense In this that caveolin-deficient mice are to Pa pneumonia due to the of Pa to invade The lipid raft-mediated uptake of Pa requires the phosphorylation of caveolin-2 by the Src family of tyrosine also observed that of the COOH-terminal Src kinase (Csk) in a in the invasion of Pa the existence of a host at invasion of to Pa, Csk to to lipid raft fractions of LECs and to phosphorylation of The of Csk in negatively regulating caveolin-2 and lipid raft-mediated Pa uptake may for the of aimed at Pa pneumonia in of caveolin-1 knock-out mice and mice and in at and to and aeruginosa and the is a that the aeruginosa in of for for in of for and on a at for with an of of Pa by R. PubMed Google Scholar). Pa a and with the A.A. J.S. J. PubMed Google Scholar). of Pa and mice with via with and and a in the to the of Pa in of the via a The with a and the mice the mice that used for of the that for the mice at by a of with The lung and in for lung in PBS, and to on by to the relative of lung by pneumonia. The to a of The of lung at The and the of the in The expressed as of the The of the in and the expressed as of the of epithelial cells both and as previously R. J.R. J. 2004; 3: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. T. Brody S.L. Am. J. 2002; PubMed Scopus Google and on with an In to previously J. Wright J.R. Am. J. Respir. Biol. 1999; PubMed Scopus Google Scholar). of with the of The cells with of Pa in of as to the number of within the epithelial cells and and murine lung epithelial cell MLE-12, by and in with and by and and to of the of with an and and sites The and to a to the cell as a and to of the in the number used to the cell The cell used to the The and with the to The caveolin-1 gene and to The caveolin-2 gene and to to and of cells to for with of cells at a of infection of cell by the addition of of in cell at for The with of the antibiotic to extracellular and for with In order to and the cells, of to for and of in and to and with an of that also to the The cell and where to the number of the of by lipid raft on invasion, in to the cells for and to the of tyrosine phosphorylation on invasion, the cells with for to infection and the of the the cells and the with in with the as The shown a of for of the invasion The of the cells not by of the used as by cells the of a and for The cells with of aeruginosa R. PubMed Google Scholar). The cells at for with to and in in the the cells with Csk and of murine with Pa also with a to the of Pa infection in with and with plasma membrane a and caveolin-2 caveolin-2 Csk Csk and tyrosine phosphorylation in a to with and for protein and in with and for by and to The proteins the Csk, and cell of cells as cells to in The cells with The cells in of The with of a of protein in for at The for at with of a of protein in the The with of and in of with and for by as and in at least and and for are as a of at least with as a of for with as a of by and in with intratracheal of Pa as a murine of pneumonia. caveolin-deficient and wild type of mice with of Pa via intratracheal and observed The to Pa pneumonia with mortality within and mortality by In the mice resistant and of the mice the and The mice and the mice not only but also the The mice at and of and lung no of of of order to the to Pa pneumonia, both of mice with of Pa and to mortality at mice infection that the of to the of both not as as the of and to mice of Pa in both the and the lung of mice of with of Pa to the and but there no the and of in the to Pa cell with and compared Pa infection no in the cell of and The cell in both and mice at Pa infection not The mice cell and a number of compared with mice a a Cytokine in also of in the mice compared with Pa infection that the mice of and lung to infection no in lung and the and mice at of not these (16Razani B. Engelman J.A. Wang X.B. Schubert W. Zhang X.L. Marks C.B. Macaluso F. Russell R.G. Li M. Pestell R.G. Di Vizio D. Hou Jr., H. Kneitz B. Lagaud G. Christ G.J. Edelmann W. Lisanti M.P. J. Biol. Chem. 2001; 276: 38121-38138Abstract Full Text Full Text PDF PubMed Scopus (258) Google it is due to the of the mice used in this compared with the Pa lung of the lung with airway and not the not by there a with lung in the the mice both of mice of pneumonia with cell the of and number of cells in the the of the mice with areas of of lung the cells, lung and In order to of the that the of and in both of mice and a of lung compared with mice to have of the compared with of the lung mice The of lung cell and of the within the Pa in LECs that the ability of Pa to within the lung is at least in to ability to invade the LECs and host defense and mice with of murine a significant number of Pa that are with the and to be in the compared with the In order to the ability of Pa to invade compared the ability of Pa to invade epithelial cells in of murine epithelial cells both the and mice R. J.R. J. 2004; 3: Full Text Full Text PDF PubMed Scopus Google Scholar). The epithelial cells with Pa for and a used to the number of epithelial cells resistant to invasion with a number of Pa compared with Pa has a ability to invade the which can serve as an important for the studies of epithelial cells not only that Pa is of invasion but also that it can survive and replicate In order to caveolin expression for uptake by both and mice and used a to Pa uptake in Unlike that Pa uptake by not in mice not Pa invasion via lipid raft-mediated endocytosis by LECs of this important and it is a of the ability of the Pa to the Caveolin-2 a of the of Pa to to both caveolin-1 and caveolin-2 expression has shown that caveolin expression is for invasion of a murine lung epithelial cell in (6Zaas D.W. Duncan M.J. Li G. Wright J.R. Abraham S.N. J. Biol. Chem. 2005; 280: 4864-4872Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). In order to the role of caveolin-1 caveolin-2 on Pa cells that caveolin-1 caveolin-2 and cells no in cell that that caveolin-1 and -2 within the cells, and within the lipid raft fractions as expected not The role of caveolin proteins in Pa invasion by uptake of Pa and cells compared with of caveolin-1 no on Pa of caveolin-2 the number of Pa We no of caveolin on the invasion of S. not We have that and not caveolin-1, is the key protein that the ability of Pa to invade and within studies have shown not only that caveolin-2 is for Pa invasion but also that it can regulate this host endocytic Pa invasion of caveolin-1 knock-out mice expression of both caveolin-1 and that the absence of caveolin-2 is the of observed in the murine by impairing invasion of Caveolin-2 the Lipid of Pa to in the Caveolin-2 with lipid rafts and Pa invasion in (6Zaas D.W. Duncan M.J. Li G. Wright J.R. Abraham S.N. J. Biol. Chem. 2005; 280: 4864-4872Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). of cells with Pa invasion that the Pa invasion in cells is due to lipid raft-mediated uptake and not a distinct lipid We that the of caveolin-2 due to role in cell signaling in the of the plasma membrane. Caveolin-2 is to a role in several cell signaling pathways and has sites of tyrosine phosphorylation (19Wang X.B. Lee H. Capozza F. Marmon S. Sotgia F. Brooks J.W. Campos-Gonzalez R. Lisanti M.P. Biochemistry. 2004; 43: 13694-13706Crossref PubMed Scopus (21) Google Scholar, H. Wang X.B. Scherer P.E. P.E. Lisanti M.P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of cells with the tyrosine kinase the number of Pa We at the of tyrosine kinase on Pa uptake by We that both and the Src family kinase Pa invasion the which is to tyrosine such as no on the number of Pa Caveolin-2 has sites of tyrosine phosphorylation at and (19Wang X.B. Lee H. Capozza F. Marmon S. Sotgia F. Brooks J.W. Campos-Gonzalez R. Lisanti M.P. Biochemistry. 2004; 43: 13694-13706Crossref PubMed Scopus (21) Google Scholar, H. Wang X.B. Scherer P.E. P.E. Lisanti M.P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In order to the role of tyrosine phosphorylation of used to both of these sites to caveolin-2 and wild type caveolin-2 expressed in to and with not of wild type caveolin-2 Pa invasion, of the to and that phosphorylation of caveolin-2 is to Pa invasion studies that Pa uptake via a lipid raft dependent by caveolin-2 expression as as tyrosine phosphorylation by Src family Csk Pa the role of signaling pathways in uptake of Pa, the in ability of of Pa, including and to invade LECs in which the expression of Csk, a Src cells to cells with an in Csk expression compared with of Csk expression no on cell not that of the Pa a of invasion cells compared with the LECs In order to the role of Csk in uptake to Pa and lipid raft-mediated invasion with that are to invade via lipid such as to Pa, observed no in the invasion of S. in the cells compared with that of Csk expression uptake of Pa via an invasion mechanism lipid raft-mediated Pa We that Csk negatively regulates the lipid raft-mediated Pa invasion of absence to of Csk the lipid raft-mediated of Pa, the of MCD, a of lipid raft-mediated invasion. We that the uptake of Pa in the cells is by with lipid raft-mediated uptake of Pa is also dependent on tyrosine the of tyrosine kinase on Pa invasion of The tyrosine kinase and the of Pa uptake in the cells that the mechanism of invasion in both and cells dependent on lipid raft and tyrosine that of Csk not a of invasion, but it lipid raft-mediated Pa invasion of Csk is to regulate members of the Src family that of Pa invasion in cells may be due to the of Csk on Src kinases that are for the phosphorylation of to the Src kinase that with caveolin-2 in lipid raft members of the Src family are within lipid and Csk S. R. Lisanti M.P. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). We caveolin-2 cells that with the caveolin-2 protein as used to which members of the Src family with We no caveolin-2 and not the of a with both and Pa infection that caveolin-2 (19Wang X.B. Lee H. Capozza F. Marmon S. Sotgia F. Brooks J.W. Campos-Gonzalez R. Lisanti M.P. Biochemistry. 2004; 43: 13694-13706Crossref PubMed Scopus (21) Google Scholar, H. Wang X.B. Scherer P.E. P.E. Lisanti M.P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). We that Csk and regulates the phosphorylation of the of Csk with no caveolin-2 and Csk at of Csk associated with caveolin-2 Pa infection Csk and caveolin-2 observed at infection and no the of caveolin-2 with and Csk an Src and Csk and for a with caveolin-2 Csk associated with caveolin-2 only Pa infection The of these Src family kinases with caveolin-2 Pa infection the important by Csk, and caveolin-2 in regulating the lipid raft-mediated uptake of the role of Csk in negatively regulating Pa the LECs to there of Pa and cells with Pa in that the of Csk expression Pa Csk at the of Pa infection on the plasma membrane and with Pa Csk is to the inactivating of this the in An of that phosphorylation of Src in the cells both and infection with Pa phosphorylation of Src to the role of Csk on caveolin-2 An of caveolin-2 that cells have phosphorylation of caveolin-2 at there is a significant in phosphorylation Pa infection Csk not only regulates the phosphorylation of but also caveolin-2 phosphorylation Pa these reveal that Csk an important role in of lipid raft-mediated Pa invasion by the phosphorylation of The ability of Csk to phosphorylation of caveolin-2 and Pa invasion of to be a host defense mechanism that is Pa The role of caveolin proteins and lipid rafts in the pathogenesis of is to be We observed a in of Pa infection and The to Pa infection associated with a but no in the of that the mice to Pa pneumonia and the role of caveolin proteins within the lung in the pathogenesis of Pa The of Pa invasion of LECs the pathogenesis of pneumonia has been the have shown that caveolin expression Pa invasion and which mortality in an pneumonia We that invasion via lipid raft-mediated uptake is an important for pathogens that within a and of host defense can as to host defense Pa is of a of pathogens that have to co-opt lipid raft-mediated endocytosis as a of host cells (10Zaas D.W. Duncan M. Rae Wright J. Abraham S.N. Biochim. Biophys. Acta. 2005; 1746: 305-313Crossref PubMed Scopus (93) Google Scholar, 11Shin J.S. Abraham S.N. Microbes Infect. 2001; 3: 755-761Crossref PubMed Scopus (109) Google and the of the caveolin-deficient mice the that invasion can to has shown that caveolin-1 is a of cell signaling pathways and that caveolin-1 of S. V. J. J. PubMed Scopus Google Scholar). studies at of in the and within the the in studies have shown that mice of in to S. V. J. J. PubMed Scopus Google Scholar). The observed in with of in the mice are most due to the in The of Pa in the caveolin-deficient mice to by of lung of and The of the mice to Pa pneumonia with the that mice are to infection with and have a mortality E. Li J. G. T.M. Pestell R.G. Lisanti M.P. Infect. Immun. PubMed Scopus Google Scholar). for these Unlike Pa, not lipid rafts for invasion of host epithelial cells, which is in the In the mice and an mice to pneumonia and Caveolin-1 knock-out mice are deficient in not only caveolin-1 but also due to the of caveolin-1 to transport caveolin-2 to the cell S. Galbiati F. Volonte D. Sargiacomo M. Engelman J.A. Scherer P.E. Lisanti M.P. 1998; PubMed Scopus Google Scholar). Our in that the of the caveolin-deficient mice is due to the absence of caveolin-2 and not caveolin-1. We have shown that only the of caveolin-2 and not caveolin-1 the Pa uptake by In caveolin-2 to be the caveolin-1 as a chaperone protein that is to caveolin-2 to the plasma membrane. In Pa invasion of requires tyrosine phosphorylation of caveolin-2 by Src family It is not caveolin-2 phosphorylation is to regulate lipid raft-mediated We have that caveolin-2 interacts with proteins, such as and the of the lipid that at the of and are for invasion. caveolin-2 as a signaling that regulates not only lipid raft-mediated endocytosis but also host to a infection and cause of for and The ability to invade host cells a to an only it the pathogen with an for but it the pathogen the of and studies have on the pathogens to host The that host cells may have to resist the of the pathogens has not been J. Li G. Duncan M.J. Abraham S.N. 2007; Full Text Full Text PDF PubMed Scopus Google that epithelial cells are to resist the of this by the and a J. Li G. Duncan M.J. Abraham S.N. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). Our studies have that LECs are also of the of Pa and that the mechanism of kinase to the phosphorylation of caveolin-2 by inactivating c-Src. In the absence of Csk, the phosphorylation of caveolin-2 and lipid of Pa in in the number of molecules Csk Pa infection is not but it is that a to Csk is also T. H. S. V. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the role of host cell signaling including caveolin-2 and Csk, has that may to in the of with Pa pneumonia. a of with this only a infection with of pneumonia. We that in that regulate the lipid raft-mediated uptake of Pa may to the to Pa pneumonia in addition to the of a of these host defense Pa infection be the of to host defense such as for have on that and have been by the of aimed at these host defense may serve as important to in