mDia2 and CXCL12/CXCR4 chemokine signaling intersect to drive tumor cell amoeboid morphological transitions.

Autor: Wyse MM; Department of Biochemistry and Cancer Biology, University of Toledo, Health Science Campus, Toledo, OH 43614, USA., Goicoechea S; Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA., Garcia-Mata R; Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA., Nestor-Kalinoski AL; Department of Surgery, University of Toledo, Health Science Campus, Toledo, OH 43614, USA., Eisenmann KM; Department of Biochemistry and Cancer Biology, University of Toledo, Health Science Campus, Toledo, OH 43614, USA. Electronic address: Kathryn.eisenmann@utoledo.edu.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2017 Mar 04; Vol. 484 (2), pp. 255-261. Date of Electronic Publication: 2017 Jan 21.
DOI: 10.1016/j.bbrc.2017.01.087
Abstrakt: Morphological plasticity in response to environmental cues in migrating cancer cells requires F-actin cytoskeletal rearrangements. Conserved formin family proteins play critical roles in cell shape, tumor cell motility, invasion and metastasis, in part, through assembly of non-branched actin filaments. Diaphanous-related formin-2 (mDia2/Diaph3/Drf3/Dia) regulates mesenchymal-to-amoeboid morphological conversions and non-apoptotic blebbing in tumor cells by interacting with its inhibitor diaphanous-interacting protein (DIP), and disrupting cortical F-actin assembly and bundling. F-actin disruption is initiated by a CXCL12-dependent mechanism. Downstream CXCL12 signaling partners inducing mDia2-dependent amoeboid conversions remain enigmatic. We found in MDA-MB-231 tumor cells CXCL12 induces DIP and mDia2 interaction in blebs, and engages its receptor CXCR4 to induce RhoA-dependent blebbing. mDia2 and CXCR4 associate in blebs upon CXCL12 stimulation. Both CXCR4 and RhoA are required for CXCL12-induced blebbing. Neither CXCR7 nor other Rho GTPases that activate mDia2 are required for CXCL12-induced blebbing. The Rho Guanine Nucleotide Exchange Factor (GEF) Net1 is required for CXCL12-driven RhoA activation and subsequent blebbing. These results reveal CXCL12 signaling, through CXCR4, directs a Net1/RhoA/mDia-dependent signaling hub to drive cytoskeleton rearrangements to regulate morphological plasticity in tumor cells. These signaling hubs may be conserved during normal and cancer cells responding to chemotactic cues.
(Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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