Myosin motor isoforms direct specification of actomyosin function by tropomyosins

Abstract

Myosins and tropomyosins represent two cytoskeletal proteins that often work together with actin filaments in contractile and motile cellular processes. While the specialized role of tropomyosin in striated muscle myosin-II regulation is well characterized, its role in non-muscle myosin regulation is poorly understood. We previously showed that fission yeast tropomyosin (Cdc8p) positively regulates myosin-II (Myo2p) and myosin-V (Myo52p) motors. To understand the broader implications of this regulation we examined the role of two mammalian tropomyosins (Tpm3.1cy/Tm5NM1 and Tpm4.2cy/Tm4) recently implicated in cancer cell proliferation and metastasis. Like Cdc8p, the Tpm3.1cy and Tpm4.2cy isoforms significantly enhance Myo2p and Myo52p motor activity, converting non-processive Myo52p molecules into processive motors that can walk along actin tracks as single molecules. In contrast to the positive regulation of Myo2p and Myo52p, Cdc8p and the mammalian tropomyosins potently inhibited skeletal muscle myosin-II, while having negligible effects on the highly processive mammalian myosin-Va. In support of a conserved role for certain tropomyosins in regulating non-muscle actomyosin structures, Tpm3.1cy supported normal contractile ring function in fission yeast. Our work reveals that actomyosin regulation by tropomyosin is dependent on the myosin isoform, highlighting a general role for specific isoforms of tropomyosin in sorting myosin motor outputs.

Distinct sites in tropomyosin specify shared and isoform‐specific regulation of myosins II and V

“… Our results with skeletal myosin II differ from those of Clayton et al () who reported that Tpm3.1 inhibits skeletal myosin II in a gliding assay. After extensive discussion and testing of each other's tropomyosin preparations we concluded the difference is due to the preparation of the gliding surface.…”

Small molecule targeting of the actin associating protein tropomyosin Tpm3.1 increases neuroblastoma cell response to inhibition of Rac‐mediated multicellular invasion

“…This therefore may explain why anti‐Tpm3.1 drugs do not phenocopy all effects of genetic deletion. Tpm3.1 recruits myosin II motors to actin filaments (Bryce et al, ; Clayton et al, ; Gateva et al, ; Schevzov et al, ) and elongated mesenchymal invasion requires inhibition of myosin II motor activity at the cell's leading edge (Asokan et al, ). Thus, continued association of Tpm3.1 with actin filaments following exposure to anti‐Tpm3.1 drugs may maintain myosin II activity at the leading edge and thereby block induction of mesenchymal invasion.…”

“…There are over 40 tropomyosin isoforms generated through differential transcript splicing from four coding genes (Gunning et al, ). Their major function is to regulate the dynamics of the associated actin filament, via regulating access of different myosin motors (Bryce et al, ; Clayton et al, ; Manstein, & Mulvihilll, ; Schevzov et al, ). Tpm3.1 stabilises actin filaments, through myosin II recruitment (Bryce et al, ; Clayton, Pollard, Murray, & Lord, 2015; Gateva et al, ; Schevzov et al, ) and this stabilising function underpins the multiplicity of roles that have been ascribed to this ubiquitously expressed protein (Bach et al, 2009; ; Bryce et al, ; Caldwell et al, ; Clayton et al, ; Lees, Bach, Bradbury, Lees et al, , 2013; Lim et al, ; Schevzov et al, ; Vlahovich et al, ).…”

Rapamycin ameliorates psoriasis by regulating the expression and methylation levels of tropomyosin viaERK1/2 andmTORpathways in vitro and in vivo

“…Tropomyosins family has long been known for its properties in the construction of cell skeleton, but it actually has shown more functions in others cell processes, such as the pathogenesis of various tumours . It is well known that the most of gene expression could be inhibited during DNA methylation.…”