3D Cellular Architecture Modulates Tyrosine Kinase Activity, Thereby Switching CD95-Mediated Apoptosis to Survival
Gülce S. Gülcüler Balta,
Cornelia Monzel,
Susanne Kleber,
Joel Beaudouin,
Emre Balta,
Thomas Kaindl,
Si Chen,
Liang Gao,
Meinolf Thiemann,
Christian R. Wirtz,
Yvonne Samstag,
Motomu Tanaka,
Ana Martin-Villalba
Affiliations
Gülce S. Gülcüler Balta
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
Cornelia Monzel
Physical Chemistry of Biosystems, Institute of Physical Chemistry, Heidelberg University, 69120 Heidelberg, Germany
Susanne Kleber
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
Joel Beaudouin
Department for Bioinformatics and Functional Genomics, Bioquant and Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 267, 69120 Heidelberg, Germany
Emre Balta
Section Molecular Immunology, Institute of Immunology, Heidelberg University, 69120 Heidelberg, Germany
Thomas Kaindl
Physical Chemistry of Biosystems, Institute of Physical Chemistry, Heidelberg University, 69120 Heidelberg, Germany
Si Chen
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
Liang Gao
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
Meinolf Thiemann
Apogenix AG, Im Neuenheimer Feld 584, 69120 Heidelberg, Germany
Christian R. Wirtz
Department of Neurosurgery, University Hospital Ulm, 89312 Günzburg, Germany
Yvonne Samstag
Section Molecular Immunology, Institute of Immunology, Heidelberg University, 69120 Heidelberg, Germany
Motomu Tanaka
Physical Chemistry of Biosystems, Institute of Physical Chemistry, Heidelberg University, 69120 Heidelberg, Germany; Corresponding author
Ana Martin-Villalba
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Corresponding author
Summary: The death receptor CD95 is expressed in every cancer cell, thus providing a promising tool to target cancer. Activation of CD95 can, however, lead to apoptosis or proliferation. Yet the molecular determinants of CD95’s mode of action remain unclear. Here, we identify an optimal distance between CD95Ligand molecules that enables specific clustering of receptor-ligand pairs, leading to efficient CD95 activation. Surprisingly, efficient CD95 activation leads to apoptosis in cancer cells in vitro and increased tumor growth in vivo. We show that allowing a 3D aggregation of cancer cells in vitro switches the apoptotic response to proliferation. Indeed, we demonstrate that the absence or presence of cell-cell contacts dictates the cell response to CD95. Cell contacts increase global levels of phosphorylated tyrosines, including CD95’s tyrosine. A tyrosine-to-alanine CD95 mutant blocks proliferation in cells in contact. Our study sheds light into the regulatory mechanism of CD95 activation that can be further explored for anti-cancer therapies. : Gülcüler Balta et al. show that CD95 receptor activation is determined through the presentation of its ligand at a certain intermolecular distance. The type of signaling triggered by CD95 is, however, decided by the cellular environment. CD95 triggers survival in cancer cells in contact with other cells and death in isolated ones. Keywords: CD95, CD95 ligand, death receptors, apoptosis, survival, cell-cell contact, cancer, tyrosine kinase, supported membrane
