Signaling Networks that Regulate Cell Migration

Abstract

SUMMARYStimuli that promote cell migration, such as chemokines, cytokines, and growth factors in metazoans and cyclic AMP in Dictyostelium, activate signaling pathways that control organization of the actin cytoskeleton and adhesion complexes. The Rho-family GTPases are a key convergence point of these pathways. Their effectors include actin regulators such as formins, members of the WASP/WAVE family and the Arp2/3 complex, and the myosin II motor protein.Pathways that link to the Rho GTPases include Ras GTPases, TorC2, and PI3K. Many of the molecules involved form gradients within cells, which define the front and rear of migrating cells, and are also established in related cellular behaviors such as neuronal growth cone extension and cytokinesis. The signaling molecules that regulate migration can be integrated to provide a model of network function. The network displays biochemical excitability seen as spontaneous waves of activation that propagate along the cell cortex. These events coordinate cell movement and can be biased by external cues to bring about directed migration.

ADiaphanous-related formin links Ras signaling directly to actin assembly in macropinocytosis and phagocytosis

“…Due to a mutation of the RasGAP neurofibromin NF1, in axenic Dictyostelium strains, excessive Ras signaling appears to bypass the requirement for fAR1-receptor activation and makes macropinocytosis constitutive, allowing the cells to grow efficiently in liquid medium (10). The links between PIP 3 and the cytoskeleton are not yet fully resolved, but several downstream effectors of this phosphoinositide, including RacGEFs and Akt, have been proposed to lead to activation of Arp2/3 complex-mediated actin assembly (63,64). Previous work demonstrated that mutants lacking PI3Ks and the small GTPases RasG and RasS display a significantly decreased large-scale endocytosis, thus supporting the view that these proteins operate in a common signaling pathway (15,34).…”

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

“…Cortical actin, approximately ~50-200-nm thick, is anchored underlying the inner face of the plasma membrane and provides a contractile force in the cortex with the presence of myosin in the network [35,36]. The cell cortex plays a critical role in cell shape changes during movement [27,37], which has been shown to stiffen as cells deform and aid the stability of shape changes [38], suggesting that the polymerization of cortical actin favors cell deformation during migration.…”

Cell Death Signaling

“…PAK2 and ROCK I are serine-threonine kinase effectors of the Rho GTPase family (Rac1, Cdc42, and Rho) that regulate actin polymerization and actin-myosin contractility. Upon caspase cleavage, their kinase activity becomes independent of the GTPases, thus inducing an aberrant reorganization of the actin cytoskeleton and the characteristic membrane blebbing observed in apoptotic cells (Rudel and Bokoch 1997;Coleman et al 2001;Sebbagh et al 2001) (for more details on cytoskeleton-modulating proteins, see Devreotes and Horwitz 2014).…”