MIEN1 drives breast tumor cell migration by regulating cytoskeletal-focal adhesion dynamics

// Marilyne Kpetemey 1, * , Pankaj Chaudhary 1, * , Timothy Van Treuren 1 , Jamboor K. Vishwanatha 1 1 Department of Molecular and Medical Genetics, Institute for Cancer Research, and the Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX 76107, USA * These authors contributed equally to this work Correspondence to: Pankaj Chaudhary, email: PankaJ.Chaudhary@unthsc.edu Keywords: MIEN1, actin polymerization, focal adhesion kinase, cofilin, migration Received: May 23, 2016      Accepted: July 13, 2016      Published: July 23, 2016 ABSTRACT Migration and invasion enhancer 1 (MIEN1) is an important regulator of cell migration and invasion. MIEN1 overexpression represents an oncogenic event that promotes tumor cell dissemination and metastasis. The underlying mechanism by which MIEN1 regulates migration and invasion has yet to be deciphered. Here, we demonstrate that MIEN1 acts as a cytoskeletal-signaling adapter protein to drive breast cancer cell migration. MIEN1 localization is concentrated underneath the actin-enriched protrusive structures of the migrating breast cancer cells. Depletion of MIEN1 led to the loss of actin-protrusive structures whereas the over-expression of MIEN1 resulted in rich and thick membrane extensions. Knockdown of MIEN1 also decreased the cell-substratum adhesion, suggesting a role for MIEN1 in actin cytoskeletal dynamics. Our results show that MIEN1 supports the transition of G-actin to F-actin polymerization and stabilizes F-actin polymers. Additionally, MIEN1 promotes cellular adhesion and actin dynamics by inducing phosphorylation of FAK at Tyr-925 and reducing phosphorylation of cofilin at Ser-3, which results in breast cancer cell migration. Collectively, our data show that MIEN1 plays an essential role in maintaining the plasticity of the dynamic membrane-associated actin cytoskeleton, which leads to an increase in cell motility. Hence, targeting MIEN1 might represent a promising means to prevent breast tumor metastasis.