Reggie-1 and -2 are two 48 kDa proteins in lipid rafts, which form homo- and hetero-oligomeric clusters in lipid raft microdomains at the cytoplasmic face of the plasma membrane and at vesicular compartments. They are evolutionary highly conserved and are present in basically all cells. The fact that reggies are located at important sites of the cells and in trafficking vesicles suggests that they might function in the delivery of cargo to specific sites.
The present thesis has investigated whether and how reggies might contribute to E-cadherin delivery to adherens junctions (AJs) at cell-cell contacts and of α5- and β1-integrins to focal adhesions (FAs) at cell-substrate contacts. surface expression of the EGFR, caused by its reduced Src-mediated phosphorylation.
Knockdown of reggie-1 thus leads to an imbalanced activation of several downstream molecules. Reggie-1 co-traffics in vesicles together with E-cadherin and reggie-1 deficiency induces an enhanced macropinocytic activity and a higher E-cadherin turnover in these cells which leads to imbalanced AJ formation and regulation.
The second part shows that reggies play an important role in protein trafficking. Reggies are part of the endocytic sorting and recycling machinery. They colocalize with Rab11a, SNX4, EHD1, TC10 and Arf6, which are all constituents of this machinery, and can directly interact with Rab11a and SNX4. Reggie-1 down-regulation impairs the localization of Rab11a to recycling-tubules and leads to a defect of transferrin receptor recycling in HeLa cells and in the recycling of E-cadherin in A431 cells. The defect in E-cadherin recycling can be partially compensated by the cells by enhanced synthesis of E-cadherin. Of note, the defective recycling can be rescued in both cell lines by a Rab11-CA mutant (and by overexpression of SNX4 in A431 cells) and can be mimicked in control cells by overexpression of a Rab11-DN mutant.
In the third part it is shown that reggie-1 also influences integrin dependent cell-substrate contacts. Reggie-1 deficient cells exhibit higher numbers of FAs in a scattered distribution and enhanced cell motility together with enhanced activation of Rac1 and FAK. In line with these observations, reggie-1 knockdown-cells display an enhanced turnover of FAs.
Reggie-105 1 co-traffics together with α5- and β1-integrins in vesicles towards FAs. Of importance, the enhanced number and scattered distribution of FAs in reggie-1 down-regulated cells can be rescued by a Rab11-CA mutant, and is mimicked in control cells with a Rab11-DN mutant construct, as seen before for the effect of reggie-1 down-regulation on E-cadherin and transferrin receptor recycling.
These data strengthen the hypothesis that reggies function together with Rab11 in the targeted transport of membrane proteins to specific sites of the cell (Stuermer, 2010).
106 7.2 Zusammenfassung
Reggie-1 und -2 sind zwei 48 kDa große „lipid raft“ Proteine, die an der Plasmamembran und in Transportvesikeln durch homo- und hetero- Oligomersierung spezielle Mikrodomänen bilden. Sie sind evolutionär hoch konserviert und in praktisch allen Zellen vorhanden. Die Beobachtung, dass Reggies sowohl an wichtigen Stellen an der Plasmamembran, als auch in Transportvesikeln vorkommen, weist darauf hin, dass diese möglicherweise am Transport von Proteinen an spezifische Stellen der Membran beteiligt sind.
In dieser Studie wurde erforscht, ob und in welcher Weise Reggies am Transport von E-Cadherin an „adherens junctions“ (AJs; Zell-Zell Kontakte) und von α5- und β1-Integrinen an Fokalkontakte (FAs; Zell-Substrat Kontakte) beteiligt sind.
Im ersten Teil dieser Studie wird gezeigt, dass Reggie-1 in Epithelzellen zusammen mit E-Cadherin (welches für die Bildung von AJs zuständig ist) und mit PrP, an Zell-Zell Kontakten akkumuliert. Zellen ohne Reggie-1 oder PrP verlieren die Eigenschaft der Kontaktinhibition und bilden weniger starke Zell-Zell Kontakte im Vergleich zu Kontrollzellen. Dieser Effekt wird hervorgerufen durch Probleme bei der Bildung und der Regulation von AJs. A431 Zellen ohne Reggie-1 weisen reduzierte Mengen an phosphoryliertem Src auf, was zu einem erhöhten Verbleib des EGF-Rezeptors an der Membran führt, da dieser dadurch weniger phosphoryliert und Aufgenommen werden kann. Die Herunterregulation von Reggie-1 führt dadurch zu einem Ungleichgewicht in der Aktivierung verschiedener Moleküle, die in der Signalkette Unterhalb des EGF-Rezeptors liegen. Reggie-1 befindet sich, zusammen mit Cadherin, an Transportvesikeln in der Zelle. Das Fehlen von Reggie-1 hat zur Folge, dass E-Cadherin vermehrt durch einen alternativen Transportweg, die Makropinozytose, aufgenommen und Recycelt wird, was zu einer erhöhten E-Cadherin Fluktuation und zu defekten AJs führt.
Im zweiten Teil wird gezeigt, dass Reggies Teil der tubulären Sortier- und Recyclings-Maschinerie der Zelle sind. Reggies lokalisieren dort zusammen mit Rab11a, SNX4, EHD1, TC10 und Arf6, welche allesamt Komponenten dieser Maschinerie darstellen. Dabei kann Reggie-1 direkt sowohl an Rab11a, als auch an SNX4 binden. Defektives Reggie-1 beeinflusst die Lokalisierung von Rab11a an das tubuläre System und verursacht Störungen im Recycling des Transferrin-Rezeptors in HeLa Zellen und im Recycling von E-Cadherin in A431 Zellen. Reggie-1 negative Zellen haben die Fähigkeit die Störung in der Formierung von Zell-Zell Kontakten zu vermindern, indem Sie die Produktion von E-Cadherin steigern.
Die Recycling-Defekte können in beiden Fällen (E-Cadherin und Transferrin Rezeptor) durch Überexpression von konstitutiv aktivem Rab11 aufgehoben werden (und durch
107 Überexpression von SNX4 in A431 Zellen). Die Expression einer dominant negativen Mutante von Rab11 kann den Effekt von fehlendem Reggie-1 in Kontrollzellen nachahmen.
Im dritten Teil wird gezeigt, dass Reggie-1 Einfluss auf die die Anzahl und die Verteilung von Fokalkontakten hat, welche Verbindungen der Zelle zum Substrat darstellen. Zellen ohne Reggie-1 weisen eine gesteigerte Phosphorylierung von FAK und eine erhöhte Aktivierung von Rac1 auf. Die Herunterregulation von Reggie führt zu gesteigerter Motilität der Zellen, einhergehend mit einem geseigerten Umbau von Fokalkontakten. Reggie-1 wird zusammen mit α5- und β1-Integrin an Fokalkontakte transportiert. Die Defekte an Zell-Substrat-Kontakten, durch Fehlendes Reggie-1, können, wie zuvor beim Recycling von E-Cadherin, durch Überexpression einer konstitutiv aktiven Rab11 Mutante aufgehoben werden.
Außerdem steigert die Überexpression einer dominant negativen Rab11 Mutante die Anzahl der Fokalkontakte in Kontrollzellen in gleicher Weise wie das Fehlen von Reggie-1.
Diese Daten stützen Hypothese, dass Reggies, zusammen mit Rab11a, am zielgerichteten Transport von Membranproteinen beteiligt sind (Stuermer, 2010).
108
8 Note on contributions
* means equal contribution
Gonzalo P. Solis*, Yvonne Schrock*, Nikola Hülsbusch*, Marianne Wiechers, Helmut Plattner and Claudia A. O. Stuermer: Reggies/flotillins regulate E-cadherin-mediated cell contact formation by affecting EGFR trafficking; Mol Biol Cell (2012).
I designed, performed, analyzed and quantified the physiological assays on the different cell lines, including the overlap of cells, the dispase-based dissociation assay and the scratch wound assay (see Figure 3.1 and Figure 3.3). Moreover, I designed, performed and analyzed the preparations of the detergent-resistant pools of E-cadherin (pre-permeabilization) and the associated localization of β-catenin and F-actin together with E-cadherin (see Figure 3.2 and Supplemental Figure S3.3). In addition I designed, performed and quantified the complete biochemical analysis of the total amount of EGFR in shLuc and shR1 cells during EGF stimulation and the corresponding analyses of the different EGFR phosphorylation sites (Figure 3.5), as well as the complete biochemical analyses of the total and phosphorylated levels of Src, PI3K, Akt, P38 and Erk1/2 (Figure 3.6). Besides I designed, performed and analyzed the localization of desmosomal structures (immunostainings) in shLuc, shR1 and shPrP cells (see Supplemental Figure S3.3). Furthermore, I designed, performed, analyzed and quantified the dextran uptake assays in shLuc, shR1 and shPrP cells (see Figure 3.7 and Supplemental Figure S3.6), as well as the dextran uptake assays in shR1 cells after treatment with DMSO, amiloride, LY294002 and the two Akt inhibitors (see Supplemental Figure S3.6). Finally, I helped to write, prepare and to finalize the manuscript.
Gonzalo P. Solis*, Nikola Hülsbusch*, Yvonne Radon*, Vladimir L. Katanaev, Helmut Plattner and Claudia A. O. Stuermer: Reggies/flotillins interact with Rab11a and SNX4 at the tubulo-vesicular recycling compartment and function in transferrin receptor and E-cadherin trafficking; Mol Biol Cell (2013).
I designed and performed the visualization of reggie-tubules by immunostaining (see Figure 4.1). In addition, I designed, performed and quantified the complete biochemical analyses of HeLa wt, shLuc and shR1 cells, including the TfR surface expression and the chloroquine assay (see Figure 4.2) as well as the biochemical analyses of A431 cells (see Supplemantal Figure S4.6). Moreover I designed and performed the co-immunuprecipitations and western blots of HA-tagged reggie-1 with
109 EGFP or ECFP tagged Rab11a, Rab4a, Rab8a, SNX4, SNX1, EHD1 and Arf6 (see Figure 4.3). Furthermore, I designed, performed and quantified the experiments for the localization of EGFP-Rab11a to tubules in HeLa shLuc and shR1 cells as well as the experiments and quantifications of Tf-rhod and R1-EGFP in the pulse-chase assay (see Figure 4.4). The complete Tf-rhod pulse chase assays in shLuc and shR1 cells after overexpression of EGFP, R1-EGFP rescue, Rab11-CA, EGFP-Rab11-DN and EGFP-Rab8a-CA were designed, perfomed, analyzed and quntified by me, as well as the biochemical analyses on Tf recycling with Tf-biotin in shLuc and shR1 cells (see Figure 4.5). In addition, I designed, performed and quantified all experiments in A431 shLuc and shR1 cells, including the analyses of E-cadherin after Ca2+-switch experiments with and without cycloheximide with microscopical and biochemical approaches (Figure 4.6) and the analyses of E-cadherin accumulations after Ca2+-switches in shLuc and shR1 cells after overexpression of control, Rab11-CA, Rab11-DN, SNX4, EHD1 and Rab8a-CA constructs (Figure 4.7), as well as the Ca2+-switch experiment with MiTMAB (Supplemental Figure S4.6). Besides, I performed the co-localization experiment in A431 cells of E-cadherin with mCherry-Rab11a and the recording of mRFP-R1 together with E-cadherin in vesicles and tubular structures in A431 cells after a Ca2+-switch (Supplemenal Figure S4.6 and Supplemental Movie S4.3). Finally, I helped to write, prepare and to finalize the manuscript.
Nikola Hülsbusch, Gonzalo P. Solis and Claudia A. O Stuermer: Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a; unpublished manuscript
I designed, performed, analyzed and quantified all experiments, except for the generation of the shR1.1 cell line. In addition I helped to write, prepare and finalize the manuscript.
110
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