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

Biochem Biophys Res Commun. 2017 Mar 4;484(2):255-261. doi: 10.1016/j.bbrc.2017.01.087. Epub 2017 Jan 21.


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.

Keywords: Amoeboid; CXCL12; Cytoskeleton; Formin.

MeSH terms

  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Chemokine CXCL12 / metabolism*
  • Formins
  • HEK293 Cells
  • Humans
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction*


  • CXCL12 protein, human
  • CXCR4 protein, human
  • Carrier Proteins
  • Chemokine CXCL12
  • DIAPH2 protein, human
  • Formins
  • Receptors, CXCR4