title: G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion.
abstract: Homotypic or entotic cell-in-cell invasion is an integrin-independent process observed in carcinoma cells exposed during conditions of low adhesion such as in exudates of malignant disease. Although active cell-in-cell invasion depends on RhoA and actin, the precise mechanism as well as the underlying actin structures and assembly factors driving the process are unknown. Furthermore, whether specific cell surface receptors trigger entotic invasion in a signal-dependent fashion has not been investigated. In this study, we identify the G-protein-coupled LPA receptor 2 (LPAR2) as a signal transducer specifically required for the actively invading cell during entosis. We find that G12/13 and PDZ-RhoGEF are required for entotic invasion, which is driven by blebbing and a uropod-like actin structure at the rear of the invading cell. Finally, we provide evidence for an involvement of the RhoA-regulated formin Dia1 for entosis downstream of LPAR2. Thus, we delineate a signaling process that regulates actin dynamics during cell-in-cell invasion.
authors.affiliation: Institute of Pharmacology, University of Marburg, Marburg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Purvanov
authors.affiliation: Institute of Pharmacology, University of Marburg, Marburg, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Holst
authors.affiliation: Institute of Pharmacology, University of Marburg, Marburg, Germany.
authors.forename: Jameel
authors.initials: J
authors.lastname: Khan
authors.affiliation: Institute of Pharmacology, University of Marburg, Marburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Baarlink
authors.affiliation: Institute of Pharmacology, University of Marburg, Marburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grosse
mesh_terms: D000199:Actins / Q000737:chemistry*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D057691:Entosis; D000080865:Formins; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein
keywords: GPCR, LPA-receptor; actin dynamics; blebbing; cell biology; cell-in-cell invasion; entosis; human; mDia1 formin