Non-Muscle Myosin II A: Friend or Foe in Cancer?

Abstract

Non-muscle myosin IIA (NM IIA) is a motor protein that belongs to the myosin II family. The myosin heavy chain 9 (MYH9) gene encodes the heavy chain of NM IIA. NM IIA is a hexamer and contains three pairs of peptides, which include the dimer of heavy chains, essential light chains, and regulatory light chains. NM IIA is a part of the actomyosin complex that generates mechanical force and tension to carry out essential cellular functions, including adhesion, cytokinesis, migration, and the maintenance of cell shape and polarity. These functions are regulated via light and heavy chain phosphorylation at different amino acid residues. Apart from physiological functions, NM IIA is also linked to the development of cancer and genetic and neurological disorders. MYH9 gene mutations result in the development of several autosomal dominant disorders, such as May-Hegglin anomaly (MHA) and Epstein syndrome (EPS). Multiple studies have reported NM IIA as a tumor suppressor in melanoma and head and neck squamous cell carcinoma; however, studies also indicate that NM IIA is a critical player in promoting tumorigenesis, chemoradiotherapy resistance, and stemness. The ROCK-NM IIA pathway regulates cellular movement and shape via the control of cytoskeletal dynamics. In addition, the ROCK-NM IIA pathway is dysregulated in various solid tumors and leukemia. Currently, there are very few compounds targeting NM IIA, and most of these compounds are still being studied in preclinical models. This review provides comprehensive evidence highlighting the dual role of NM IIA in multiple cancer types and summarizes the signaling networks involved in tumorigenesis. Furthermore, we also discuss the role of NM IIA as a potential therapeutic target with a focus on the ROCK-NM IIA pathway.

Keywords: MYH9; motor protein; myosin IIA; non-muscle myosin IIA; tumorigenesis.

Figure 2

This figure illustrates the two assembly states of non-muscle myosin II (NMII): the 10S assembly-incompetent state and the 6S assembly-competent state. In the 10S assembly-incompetent state (left), the myosin molecule is folded, with the globular head and heavy chain regions interacting through various tail-binding sites, leading to a compact structure. Many intramolecular interactions keep the 10S state in an inactive stable form (Table 1). The interactions involve the Blocked Head (BH), which is the myosin head prevented from binding to actin, and the Free Head (FH), another myosin head that is inhibited but not directly involved in actin binding in the 10S state. The transition to the 6S assembly-competent state (right) occurs upon the phosphorylation of the regulatory light chain (RLC), resulting in an extended, active conformation where the heavy chain regions are aligned, allowing for actin binding and ATPase activity, which are essential for NMII’s role in cell contractility and motility. ELC: Essential Light Chain; RLC: Regulatory Light Chain; FH: Free Head; BH: Blocked Head; TF: Tail–Free Head Interaction; TB: Tail–Blocked Head Interaction; TT: Tail–Tail Interaction.

Figure 1

The expression and alteration profile of MYH9 at the pancancer level. (A) MYH9 mRNA expression from 32 TCGA datasets. (B) The alteration profile of MYH9 from the same 32 TCGA datasets. The expression and alteration frequency data were obtained from cBioPortal (www.cbioportal.org).

Figure 3

The figure shows the specific kinases involved in the phosphorylation of serine and threonine residues of both RLCs and heavy chains. PKC, protein kinase C; MLCK, myosin light chain kinase; ROCK, Rho-associated protein kinase; TRPM7, transient receptor potential melastatin 7; PKCβ, protein kinase Cβ; CK II, casein kinase II. The figure was adapted from Pecci et al. [28].

Figure 4

This figure illustrates the regulation of myosin II filament formation and activity. Specific serine residues on the myosin heavy chain (S1916, S1927, and S1943) are phosphorylated by various kinases, including MHCKA, MHCKB, MHCKC, TRPM6, TRPM7, PKC, and CK2. The phosphorylation of these sites is depicted as favoring the filamentous state of myosin, which is essential for mechanotransduction and ATP hydrolysis-driven interaction with actin filaments. Phosphatases are the enzymes responsible for dephosphorylation, which may reverse the phosphorylation effect, potentially leading to a shift back to the monomeric state of myosin. Mts1, also known as S100A4, is a calcium-binding protein that regulates myosin II function by modulating filament assembly. It binds to the myosin heavy chain, influencing the balance between monomeric and filamentous forms of myosin II. Mts1 typically inhibits filament formation, thereby controlling myosin’s contractile activity and its ability to interact with actin.

Figure 5

The figure shows the structure and orientation of cell migration in the 2D environment. At the front, actin filaments within lamellipodia and filopodia are oriented with their rapidly polymerizing ends in the forward direction. In the main body, actin and myosin filaments form bipolar structures to aid in cell retraction. NM IIA and NM IIB show distinct localizations inside the cell, with NM IIA predominantly being found at the leading edge where actin dynamics are most active. NM IIB is predominant toward the rear end. The region between the leading and trailing edges contains varying concentrations of NM IIA and NM IIB. Additional molecules, such as RhoA, Rac1, Cdc42, Ca²⁺ ions, and αPKC, also play significant roles in this cellular organization and migration process.

Figure 6

The formation of plasma membrane blebs consists of three phases: initiation, expansion, and retraction. Blebbing stimuli, such as Ca²⁺ influx and apoptosis, induce the initiation of membrane protrusion. Actomyosin contractility drives the expansion of blebs, which are devoid of the F-actin cortex. Rho-ROCK signaling then drives bleb retraction via actomyosin contractility. NM IIA contractile forces promote bleb retraction.

Figure 7

A schematic representation of the MYH9 exons with common mutations found in patients with MYH9-RD. The color coding of exon organization is as follows: black, motor domain; green, neck; orange, coiled coil domain; and brown, non-helical tail.