Forces and signal transduction by desmosomal cadherins

• Applicant: Professor Dr. Volker Spindler
• Subject Area: Biophysics ; Nuclear Medicine, Radiotherapy, Radiobiology ; Cell Biology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290004423

• Final Report Year: 2021

Final Report Abstract

The aim of this grant was to identify inside-out and outside-in regulators of desmosomal adhesion.The main projects of this grant could be addressed. The results reveal novel regulatory mechanisms of desmosomal adhesion by the intermediate and the actin cytoskeleton and by desmosomal adapter molecules. One important result is that different proteins influence distinct aspects of desmosome function. While the cortical actin cytoskeleton fosters nascent desmosome formation, keratins and plakophilins modulate the binding properties of desmosomal molecules on single molecule level, at least in part through their regulatory impact on signaling molecules such as p38MAPK or PKC. In contrast, desmoplakin does not impact desmosomal cadherin binding but modulates clustering in the membrane, which is required to form stable intercellular adhesion. Together, the results reveal a complex regulatory network in which specific structural molecules, in part dependent on signaling, modulate distinct aspects of desmosome turnover and function. Vice versa, cells react to loss of specific molecules with a differentiated response with regard to activity of signaling molecules. Together, the data corroborate our understanding that desmosomes and specific desmosomal molecules modulate cell behavior by integrating intracellular and extracellular signals. These results are relevant for the understanding of severe diseases such as pemphigus or arrhythmogenic cardiomyopathies.

Publications

• (2017). Inhibition of p38MAPK signaling prevents epidermal bistering and alteration of desmosome structure induced by pemphigus autoantibodies in human epidermis Br J Dermatol. 177(6):1612-1618
  Egu DT, Walter E, Spindler V, Waschke J
  
• (2017). Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells. Mol Carcinogenesis; 56(8):1884-1895
  Hütz K, Zeiler J, Sachs L, Ormanns, S, Spindler V
  
• (2018). Keratin Retraction and Desmoglein3 Internalization Independently Contribute to Autoantibody-Induced Cell Dissociation in Pemphigus Vulgaris. Front Immunol. 9:858
  Schlögl E, Radeva MY, Vielmuth F, Schinner C, Waschke J, Spindler V
  
• (2018). Keratins regulate the adhesive properties of desmosomal cadherins through signaling. J Invest Dermatol 138(1):121-131
  Vielmuth F, Wanuske MT, Radeva MY, Hiermaier M, Kugelmann D, Walter E, Buechau F, Magin TM, Waschke J, Spindler V
  
• (2018). Mechanisms Causing Loss of Keratinocyte Cohesion in Pemphigus. J Invest Dermatol, 138(1):32-37
  Spindler V, Eming R, Schmidt E, Amagai M, Grando S, Jonkman MF, Kowalczyk AP, Müller EJ, Payne AS, Pincelli C, Sinha AA, Sprecher E, Zillikens D, Hertl M, Waschke J
  
• (2019). Plakophilin 1 but not plakophilin 3 regulates desmoglein clustering. Cell Mol Life Sci 76, 3465–3476
  Fuchs M, Foresti M, Radeva MY, Kugelmann D, Keil R, Hatzfeld M, Spindler V, Waschke J, Vielmuth F
  
• (2020). The actin-binding protein alpha-aducin modulates desmosomal turnover and function. J Invest Dermatol.
  Hiermaier M, Kliewe F, Schinner C, Stüdle C, Maly IP, Wanuske MT, Rötzer V, Endlich N, Vielmuth F, Waschke J, Spindler V
  
• (2021). Clustering of desmosomal cadherins by desmoplakin is essential for cell-cell adhesion. Acta Physiol, 231(4):e13609
  Wanuske MT, Brantschen D, Schinner C, Stüdle C, Walter E, Hiermaier M, Vielmuth F, Waschke J, Spindler V