Non-muscle myosin II in disease: mechanisms and therapeutic opportunities

Abstract

The actin motor protein non-muscle myosin II (NMII) acts as a master regulator of cell morphology, with a role in several essential cellular processes, including cell migration and post-synaptic dendritic spine plasticity in neurons. NMII also generates forces that alter biochemical signaling, by driving changes in interactions between actin-associated proteins that can ultimately regulate gene transcription. In addition to its roles in normal cellular physiology, NMII has recently emerged as a critical regulator of diverse, genetically complex diseases, including neuronal disorders, cancers and vascular disease. In the context of these disorders, NMII regulatory pathways can be directly mutated or indirectly altered by disease-causing mutations. NMII regulatory pathway genes are also increasingly found in disease-associated copy-number variants, particularly in neuronal disorders such as autism and schizophrenia. Furthermore, manipulation of NMII-mediated contractility regulates stem cell pluripotency and differentiation, thus highlighting the key role of NMII-based pharmaceuticals in the clinical success of stem cell therapies. In this Review, we discuss the emerging role of NMII activity and its regulation by kinases and microRNAs in the pathogenesis and prognosis of a diverse range of diseases, including neuronal disorders, cancer and vascular disease. We also address promising clinical applications and limitations of NMII-based inhibitors in the treatment of these diseases and the development of stem-cell-based therapies.

Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells

“…This positive feedback mechanism on Src would be expected to cause the subsequent decrease in stress fibre-dependent contractility allowing for cell migration. However, we cannot exclude that the effect of inhibiting Myosin II activity on ERK-dependent cell proliferation is independent of the polarized stress fibres by EVL, as Myosin II activity controls several essential cellular processes47.…”

Septin-regulated actin dynamics promoteSalmonellainvasion of host cells

“…Nonmuscle myosin II is a major contributor to cellular organisation and regulation. Myosins are able to crosslink and bundle actin filaments to promote contraction forces capable of deforming cell membranes in processes such as cell migration and phagocytosis (Newell‐Litwa, Horwitz, & Lamers, ). Prior studies by Stradal and colleagues characterised a RhoA/Myosin II‐dependent pathway of actin rearrangement during S .…”

Blebbistatin reveals beneficial effects on the cystometric parameters in an animal model of detrusor overactivity

“…Blebbistatin (BLEB) has been discovered with the aid of a high-throughput molecule screen for inhibitors of nonmuscle myosin II (Straight et al 2003). Furthermore, it was demonstrated that BLEB inhibits both nonmuscle and muscle myosins (Newell-Litwa et al 2015). Moreover, it was demonstrated that BLEB inhibiting potential is higher toward the SM-B (which is present in higher amounts in the urinary bladder (Andersson and Arner 2004)) compared to the SM-A type (Rhee et al 2006) (which is found in lower abundance in the bladder (Andersson and Arner 2004)).…”