Cellular Motility Driven by Assembly and Disassembly of Actin Filaments

Approximately one percent of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho family of small GTPases. Through a series of complex biochemical networks, these highly conserved molecular switches control some of the most fundamental processes of cell biology common to all eukaryotes, including morphogenesis, polarity, movement, and cell division. In the first part of this review, we present the best characterized of these biochemical pathways; in the second part, we attempt to integrate these molecular details into a biological context.

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Rho GTPases: Biochemistry and Biology

Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

Rho GTPases and their effector proteins.

Somlyo, Andrew P., and Avril V. Somlyo. Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase. Physiol Rev 83: 1325-1358, 2003; 10.1152...

https://www.physiology.org/doi/pdf/10.1152/physrev.00023.2003

Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase

ROCKs, or Rho kinases, are serine/threonine kinases that are involved in many aspects of cell motility, from smooth-muscle contraction to cell migration and neurite outgrowth. Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states.

ROCKs: multifunctional kinases in cell behaviour

Rac is a small GTPase of the Rho family that mediates stimulus-induced actin cytoskeletal reorganization to generate lamellipodia Little is known about the signalling pathways that link Rac activation to changes in actin filament dynamics Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3; however, the kinases responsible for this phosphorylation have not been identified Here we show that LIM-kinase 1 (LIMK-1), a serine/threonine kinase containing LIM and PDZ domains, phosphorylates cofilin at Ser 3, both in vitro and in vivo When expressed in cultured cells, LIMK-1 induces actin reorganization and reverses cofilin-induced actin depolymerization Expression of an inactive form of LIMK-1 suppresses lamellipodium formation induced by Rac or insulin Furthermore, insulin and an active form of Rac increase the activity of LIMK-1 Taken together, our results indicate that LIMK-1 participates in Rac-mediated actin cytoskeletal reorganization, probably by phosphorylating cofilin

Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization

http://www.jbc.org/content/275/5/3577.full.pdf

Rho-associated Kinase ROCK Activates LIM-kinase 1 by Phosphorylation at Threonine 508 within the Activation Loop

https://www.jbc.org/content/271/47/30022.full.pdf

Kyoko Nagata

Papers

Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization

Rho-associated Kinase ROCK Activates LIM-kinase 1 by Phosphorylation at Threonine 508 within the Activation Loop

Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases

Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6.

Stimulation of Sky Receptor Tyrosine Kinase by the Product of Growth Arrest-specific Gene 6