title: mDia2 and CXCL12/CXCR4 chemokine signaling intersect to drive tumor cell amoeboid morphological transitions.
abstract: 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.
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, Health Science Campus, Toledo, OH 43614, USA.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Wyse
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Goicoechea
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Garcia-Mata
authors.affiliation: Department of Surgery, University of Toledo, Health Science Campus, Toledo, OH 43614, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Nestor-Kalinoski
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, Health Science Campus, Toledo, OH 43614, USA. Electronic address: Kathryn.eisenmann@utoledo.edu.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Eisenmann
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080865:Formins; D057809:HEK293 Cells; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D002352:Carrier Proteins; D054377:Chemokine CXCL12; C491462:DIAPH2 protein, human; D000080865:Formins; D019718:Receptors, CXCR4
keywords: Amoeboid; CXCL12; Cytoskeleton; Formin