The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

Abstract

The contractile actin-myosin cytoskeleton provides much of the force required for numerous cellular activities such as motility, adhesion, cytokinesis and changes in morphology. Key elements that respond to various signal pathways are the myosin II regulatory light chains (MLC), which participate in actin-myosin contraction by modulating the ATPase activity and consequent contractile force generation mediated by myosin heavy chain heads. Considerable effort has focussed on the role of MLC kinases, and yet the contributions of the myotonic dystrophy-related Cdc42-binding kinases (MRCK) proteins in MLC phosphorylation and cytoskeleton regulation have not been well characterized. In contrast to the closely related ROCK1 and ROCK2 kinases that are regulated by the RhoA and RhoC GTPases, there is relatively little information about the CDC42-regulated MRCKα, MRCKβ and MRCKγ members of the AGC (PKA, PKG and PKC) kinase family. As well as differences in upstream activation pathways, MRCK and ROCK kinases apparently differ in the way that they spatially regulate MLC phosphorylation, which ultimately affects their influence on the organization and dynamics of the actin-myosin cytoskeleton. In this review, we will summarize the MRCK protein structures, expression patterns, small molecule inhibitors, biological functions and associations with human diseases such as cancer.

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

“…Chelerythrine, originally identified as a PKC inhibitor with in vitro IC50 of 660 nM (54), was subsequently shown to inhibit MRCKα kinase activity with an in vitro IC50 of 1.77 µM (55). Other off-target effects have also been found for chelerythrine, such as reactive oxygen species generation, DNA intercalation and inhibition of acetylcholinesterases, making this compound difficult for use for identifying MRCK functions (30). Another compound, the natural product cycloartane 3,24,25-triol, was discovered as a potential MRCKα inhibitor (56) due to its ability to compete an immobilized ligand for binding to the ATP-binding site.…”

“…In addition, MRCKα induced phosphorylation of moesin in vitro (29), which links integral membrane proteins to filamentous actin, suggesting that actin-myosin contractility may be further promoted by MRCK through enhanced coupling of the cytoskeleton to the membrane. Elevated MRCK expression has been found in various cancer cells, such as lymphoma, breast cancer, lung cancer, and pancreatic adenocarcinoma (30). …”

ICAP-1 monoubiquitylation coordinates matrix density and rigidity sensing for cell migration through ROCK2–MRCKα balance

“…So far, how ICAP-1 can regulate both RhoA-ROCK signaling and the Cdc42 and Rac1 pathway was unclear. It has been described that a cooperation between RhoA-ROCK and Cdc42 or Rac1-MRCK signaling can control cell contractility cell polarity, morphology and morphogenesis (Gally et al, 2009;Unbekandt and Olson, 2014;Wilkinson et al, 2005). Their respective contribution might depend on ECM rigidity.…”

Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), the ROCK-like effectors of Cdc42 and Rac1

“…MRCK has been found in a number of contexts to promote cancer cell motility and invasiveness as recently reviewed. 80 Cdc42 plays an important role in establishing cell polarity in a number of contexts, and its disregulation can be a factor in cancer progression. 81 The actin-myosin contraction regulated by MRCK aids re-orientation of cell nuclei relative to microtubuleorganizing center (MTOC), and this help establish the forward polarity of the Golgi apparatus in migrating cells.…”