Lehrstuhl I Anatomie
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Inhaltsbereich

AG Prof. Waschke

The main focus of our research groups is cell cohesion and signaling. Intercellular adhesion mediated by adhesive contacts such as desmosomes and adherens junctions (AJ) is essential for coordinated function of cells in tissues as well as for the formation of epithelial and endothelial barriers. In these adhesive contacts the main adhesion molecules belong to the cadherin superfamily. Strong adhesion is most important in tissues exposed to high degrees of mechanical stress such as the epidermis or the myocardium. Cell-cell adhesion needs to be tightly controlled by signaling pathways to facilitate tissue integrity but also to permit tissue differentiation and repair. Therefore, for a long a time we thought of cell contacts primarily as targets of signaling cues. In our early work we found that the endothelial barrier is tightly regulated by a pathway comprised of the second messenger cAMP and the small GTPase Rac1 (1, 2) and that this signaling pathway is impaired in inflammation and sepsis (3). However, similar to AJ we became aware that desmosomal contacts besides their mechanical function provide the structural basis for signaling hubs. This knowledge came from the observations that autoantibodies targeting desmosomal cadherins in pemphigus can induce loss of cell cohesion independent of direct interfering with the adhesive interface of desmosomal cadherins (4, 5). Rather, autoantibodies modulate signaling pathways such as Rho GTPases or p38MAPK, the latter of which we identified to form an adhesive-dependent signaling complex with Dsg3 and plakoglobin (6, 7, 8). Since patients with pemphigus often suffer from Dry eye syndrome, we started a project on regulation of cell adhesion in Meibomian gland cells (12). Because we found that Dsg2 interaction is required for intestinal epithelial barrier integrity (9) and cardiomyocyte cohesion and function (10), in we characterize the mechanisms by which Dsg2 contributes to the pathogenesis of Crohn’s disease (11, 13) as well as to arrhythmogenic cardiomyopathy (14). .

 

  1. Waschke J, Baumgartner W, Adamson RH, Zeng M, Aktories K, Barth H, Wilde C, Curry FE, Drenckhahn D (2004) Requirement of Rac activity for maintenance of capillary endothelial barrier properties. Am. J. Physiol. Heart Circ. Physiol. 286: H394-401
  2. Waschke J, Drenckhahn D, Adamson RH, Barth H, Curry FE (2004) cAMP protects endothelial barrier functions by preventing Rac-1 inhibition. Am. J. Physiol. Heart Circ. Physiol. 287: H2427-433
  3. Schlegel N, Baumer Y, Drenckhahn D, Waschke J (2009) LPS-induced endothelial barrier breakdown is cAMP-dependent in vivo and in vitro. Crit. Care Med., 37(5): 1735-43
  4. Waschke J, Bruggeman P, Baumgartner W, Zillikens D, Drenckhahn D (2005) Pemphigus foliaceus IgG cause dissociation of desmoglein 1-containing junctions without blocking desmoglein 1 transinteraction. J. Clin. Invest. 115(11):3157-65
  5. Heupel WM, Zillikens D, Drenckhahn D, Waschke J (2008) Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction. J. Immunol., 181(3):1825-1834
  6. Waschke J, Spindler V, Bruggeman P, Zillikens D, Schmidt G, Drenckhahn D (2006) Inhibition of Rho A activity causes pemphigus skin blistering. J. Cell Biol., 175(5): 721-7
  7. Spindler V, Rötzer V, Dehner C, Kempf B, Gliem M, Radeva M, Hartlieb E, Harms G, Schmidt E, Waschke J (2013) Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering, J. Clin. Invest., 123(2):800-811
  8. Spindler V, Dehner C, Hübner S, Waschke J. (2014). Plakoglobin but Not Desmoplakin Regulates Keratinocyte Cohesion via Modulation of p38MAPK Signaling. J Invest Dermatol. 2014 Jun;134(6):1655-64
  9. Schlegel N, Meir M., Heupel WM, Holthöfer B, Leube R, Waschke J (2010) Desmoglein 2-mediated adhesion is required for intestinal epithelial barrier integrity. AJP Gastrointestinal and Liver Physiology ,298(5):774-783
  10. Schlipp A, Schinner C, Spindler V, Vielmuth F, Gehmlich K, Syrris P, McKenna WJ, Dendorfer A, Hartlieb E, Waschke J. (2014) Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. Cardiovasc Res, 104(2):245-57
  11. Spindler V, Meir M, Vigh B, Flemming S, Hütz K, Germer CT, Waschke J, Schlegel N (2015). Loss of desmoglein2 contributes to the pathogenesis of Crohn’s disease. Inflamm Bowel Dis, 21(10):2349-59
  12. Rötzer V, Egu D, Waschke J (2016). Meibomian gland cells display a differentiation-dependent composition of desmosomes. Histochem Cell Biol. 2016;146:685-694
  13. Ungewiß H, Vielmuth F, Suzuki ST, Maiser A, Harz H, Leonhardt H, Kugelmann D, Schlegel N, Waschke J (2017) Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase. Sci Rep., 7(1):6329.
  14. Schinner C, Vielmuth F, Rötzer, V, Hiermaier M, Radeva M, Co TK, Hartlieb E, Schmidt A, Imhof A, Messoudi A, Horn A, Schlipp A, Spindler V, Waschke J (2017) Adrenergic signaling strengthens cardiac myocyte cohesion, Circ Res.120(8):1305-1317

 

Projects of Jens Waschke:

Epidermal cell cohesion and pemphigus
Endothelial barrier dysfunction and inflammation
Regulation of cardiomyocyte cohesion and arrhythmogenic cardiomyopathy
Intestinal epithelial barrier regulation and Crohn’s disease
Cell adhesion in Meibomian gland cells and Dry eye syndrom