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

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.

Cell matrix adhesions in cancer: The proteins that form the glue

“…The oncogene Migration and invasion enhancer 1 (MIEN1) regulates cell migration by inducing phosphorylation of FAK at Tyr-925 [ 51 ]. MIEN1 is located in the chromosomal region 17q12-21 and is typically amplified along with its neighboring gene ERBB2 in breast cancer [ 52 ].…”

“…MIEN1 is located in the chromosomal region 17q12-21 and is typically amplified along with its neighboring gene ERBB2 in breast cancer [ 52 ]. Its many functions include regulating Actin cytoskeletal dynamics and influencing expression of ECM-degrading proteases and angiogenic factors [ 51 , 53 ]. Down regulation of MIEN1 leads to a reduction in FAK phosphorylation at Tyr-925, as well as reduced phosphorylation of Akt, Erk1/2 and NF-κB [ 51 ].…”

“…Its many functions include regulating Actin cytoskeletal dynamics and influencing expression of ECM-degrading proteases and angiogenic factors [ 51 , 53 ]. Down regulation of MIEN1 leads to a reduction in FAK phosphorylation at Tyr-925, as well as reduced phosphorylation of Akt, Erk1/2 and NF-κB [ 51 ]. Analysis of FAK activation is of paramount importance to any FA signaling study.…”

“…Analysis of FAK activation is of paramount importance to any FA signaling study. Many FAK-activating proteins have been characterized, including p130RhoGEF [ 45 ], PDGF [ 46 ] and MIEN1 [ 51 ], however, the complexity of this signaling pathway suggests that multiple other factors are waiting to be discovered.…”

Characterizing functional consequences of DNA copy number alterations in breast and ovarian tumors by spaceMap

“…Migration and invasion enhancer 1 (MIEN1) is an important regulator of cell migration and invasion. In a recently reported study, MIEN1 is found to drive breast tumor cell migration by regulating cytoskeletal-focal adhesion dynamics, and targeting MIEN1 is suggested to be a promising means to prevent breast tumor metastasis (Kpetemey et al, 2016). KAT2A, also known as histone acetyltransferase GCN5, is reported to play an essential role in the HBXIP-enhanced migration of breast cancer cells by wound healing assay, and thus is also an important player in tumor metastasis of breast cancer (Li et al, 2015).…”