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

Abstract

Cdc42 is a member of the Rho GTPase protein family that plays key roles in local F-actin organization through a number of kinase and non-kinase effector proteins. The myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs), and the RhoA binding coiled-coil containing kinases (ROCKs) are widely expressed members of the Dystrophia myotonica protein kinase (DMPK) family. The MRCK proteins are ∼190 kDa multi-domain proteins expressed in all cells and coordinate certain acto-myosin networks. Notably MRCK is a key regulator of myosin18A and myosin IIA/B, and through phosphorylation of their common regulatory light chains (MYL9 or MLC2) to promote actin stress fiber contractility. The MRCK kinases are regulated by Cdc42, which is required for cell polarity and directional migration; MRCK links to the acto-myosin complex through interaction with a coiled-coil containing adaptor proteins LRAP35a/b. The biological activities of MRCK in model organisms such as worms and flies confirm it as a myosin II activator. In mammalian cell culture MRCK can be critical for cancer cell migration and neurite outgrowth. We review the current literatures regarding MRCK and highlight the similarities and differences between MRCK and ROCK kinases.

MRCK-1 Drives Apical Constriction in C. elegans by Linking Developmental Patterning to Force Generation

“…Unlike traditional myosin light chain kinases, MRCK-family kinases and Rho-associated kinases are not regulated by calcium binding. Instead their activities are modulated by interaction with the Rho family small GTPases and other binding partners [26, 27]. …”

Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin

“…Cdc42 is linked to myosin activation via the myotonic dystrophy kinase-related MRCK kinases (reviewed in [19]), suggesting that pseudopod retraction defects may be due to reduced activation of myosin light chain (MLC). However, levels of MLC phosphorylation at T18/S19 were unaltered in Cdc42 null melanocytes (Figures S4D and S4E).…”

Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton

“…The Cdc42 target responsible for thin bundle reorganization via tricellulin-Tuba partnership in epithelia is not known. A likely candidate is MRCK, a kinase effector of Cdc42, that associates with acto-myosin filaments and, similar to ROCKI/II, phosphorylates myosin regulatory chain [85]. In endothelial cells, MRCK is activated upon induction of cell-cell contacts and controls how compact and aligned circumferential bundles are towards junctions [86].…”