mDia2 and CXCL12/CXCR4 chemokine signaling intersect to drive tumor cell amoeboid morphological transitions.
mDia2 and CXCL12/CXCR4 chemokine signaling intersect to drive tumor cell amoeboid morphological transitions.
复制标题
mDia2 和 CXCL12/CXCR4 趋化因子信号交叉驱动肿瘤细胞变形虫形态转变。
DOI：
10.1016/j.bbrc.2017.01.087
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发表时间：
2017
影响因子：
3.1
通讯作者：
Eisenmann,KathrynM
中科院分区：
文献类型：
--
作者：
Wyse,MeghanM;Goicoechea,Silvia;Garcia-Mata,Rafael;Nestor-Kalinoski,AndreaL;Eisenmann,KathrynM
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.
