Myosin II isoform switching mediates invasiveness after TGF-β-induced epithelial-mesenchymal transition.
Despite functional significance of nonmuscle myosin II in cell migration and invasion, its role in epithelial-mesenchymal transition (EMT) or TGF-β signaling is unknown. Analysis of normal mammary gland expression revealed that myosin IIC is expressed in luminal cells, whereas myosin IIB expression is up-regulated in myoepithelial cells that have more mesenchymal characteristics. Furthermore, TGF-β induction of EMT in nontransformed murine mammary gland epithelial cells results in an isoform switch from myosin IIC to myosin IIB and increased phosphorylation of myosin heavy chain (MHC) IIA on target sites known to regulate filament dynamics (S1916, S1943). These expression and phosphorylation changes are downstream of heterogeneous nuclear ribonucleoprotein-E1 (E1), an effector of TGF-β signaling. E1 knockdown drives cells into a migratory, invasive mesenchymal state and concomitantly up-regulates MHC IIB expression and MHC IIA phosphorylation. Abrogation of myosin IIB expression in the E1 knockdown cells has no effect on 2D migration but significantly reduced transmigration and macrophage-stimulated collagen invasion. These studies indicate that transition between myosin IIC/myosin IIB expression is a critical feature of EMT that contributes to increases in invasive behavior.
Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195, USA.
Jordan R
JR
Beach
George S
GS
Hussey
Tyler E
TE
Miller
Arindam
A
Chaudhury
Purvi
P
Patel
James
J
Monslow
Qiao
Q
Zheng
Ruth A
RA
Keri
Ofer
O
Reizes
Anne R
AR
Bresnick
Philip H
PH
Howe
Thomas T
TT
Egelhoff
D000818:Animals; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D051379:Mice; D024462:Myosin Type II / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; D024462:Myosin Type II