Current Molecular Medicine (v.14, #2)

Editorial (Thematic Issue: Signaling in Cell Migration and Disease) by Lisette Leyton, Vicente A. Torres, Andrew F.G. Quest (197-198).

Regulation of RhoA Activity by Adhesion Molecules and Mechanotransduction by R.J. Marjoram, E.C. Lessey, K. Burridge (199-208).
The low molecular weight GTP-binding protein RhoA regulates many cellular events, including cellmigration, organization of the cytoskeleton, cell adhesion, progress through the cell cycle and gene expression.Physical forces influence these cellular processes in part by regulating RhoA activity throughmechanotransduction of cell adhesion molecules (e.g. integrins, cadherins, Ig superfamily molecules). RhoAactivity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs)that are themselves regulated by many different signaling pathways. Significantly, the engagement of manycell adhesion molecules can affect RhoA activity in both positive and negative ways. In this brief review, weconsider how RhoA activity is regulated downstream from cell adhesion molecules and mechanical force.Finally, we highlight the importance of mechanotransduction signaling to RhoA in normal cell biology as well asin certain pathological states.

Wnt Signaling and Cell-Matrix Adhesion by P. Astudillo, J. Larrain (209-220).
Three decades after the beginning of the study of the Wnt signaling pathway, major contributionshave been made to elucidate the molecular mechanisms that regulate this signaling pathway and its role indevelopment, homeostasis and disease. However, there is still a lack of understanding about the relationshipsbetween Wnt signaling and cell-extracellular matrix (ECM) adhesion. Data gathered in the last years is helpingto uncover these relationships. Several ECM proteins are able to regulate components of the Wnt pathwayduring development and disease, and their misregulation leads to changes in Wnt signaling. Fibronectin, amajor ECM protein, regulates non-canonical Wnt signaling during embryogenesis in Xenopus and in muscleregeneration in mouse, whereas it modulates canonical Wnt signaling through modulation of β -catenin.Integrins, which act as Fibronectin receptors, also modulate Wnt activity, and Syndecan-4, a heparan sulphateproteoglycan, is able to regulate canonical and non-canonical Wnt pathways, notably during embryogenesis.Other secreted ECM proteins have been recently associated to the regulation of Wnt signaling, albeitmolecular mechanisms are still unclear. The non-canonical Wnt pathway plays a role in the regulation of theECM assembly, and modulates focal adhesion dynamics through the involvement of Wnt components,whereas Wnt/β-catenin signaling regulates the expression of genes encoding ECM proteins. This evidenceindicates that Wnt signaling and cell-ECM adhesion are two closely related processes, and alterations in thiscross-talk might be involved in disease.

RhoGEFs in Cell Motility: Novel Links Between Rgnef and Focal Adhesion Kinase by N.L.G. Miller, E.G. Kleinschmidt, D.D. Schlaepfer (221-234).
Rho guanine exchange factors (GEFs) are a large, diverse family of proteins defined by their abilityto catalyze the exchange of GDP for GTP on small GTPase proteins such as Rho family members. GEFs actas integrators from varied intra- and extracellular sources to promote spatiotemporal activity of Rho GTPasesthat control signaling pathways regulating cell proliferation and movement. Here we review recent studieselucidating roles of RhoGEF proteins in cell motility. Emphasis is placed on Dbl-family GEFs and connectionsto development, integrin signaling to Rho GTPases regulating cell adhesion and movement, and how thesesignals may enhance tumor progression. Moreover, RhoGEFs have additional domains that confer distinctivefunctions or specificity. We will focus on a unique interaction between Rgnef (also termed Arhgef28 orp190RhoGEF) and focal adhesion kinase (FAK), a non-receptor tyrosine kinase that controls migrationproperties of normal and tumor cells. This Rgnef-FAK interaction activates canonical GEF-dependent RhoAGTPase activity to govern contractility and also functions as a scaffold in a GEF-independent manner toenhance FAK activation. Recent studies have also brought to light the importance of specific regions within theRgnef pleckstrin homology (PH) domain for targeting the membrane. As revealed by ongoing Rgnef-FAKinvestigations, exploring GEF roles in cancer will yield fundamental new information on the molecularmechanisms promoting tumor spread and metastasis.

On the Role of Rab5 in Cell Migration by P. Mendoza, J. Diaz, V.A. Torres (235-245).
Uncontrolled endosome trafficking is a common feature of certain cancer cells, which has beenacknowledged during the last decade. Migration and invasiveness of metastatic tumor cells are both regulatedby components of the endocytic machinery, including Rab proteins. Rab GTPases are essential in processesof endosome fusion, as well as targeting, tethering and transport along the cytoskeleton. In addition to thiscanonical role, some Rabs depict other functions, such as controlling cell proliferation, apoptosis, adhesion andmotility. Here, we review our current knowledge on the role of Rab5, a key regulator of early endosomedynamics, in migration of normal and tumor cells. Rab5 promotes cell migration in vitro and in vivo bymechanisms described at different levels. One such mechanism is by controlling the rates of integrininternalization and recycling, thereby affecting its activation and availability at the cell surface. On the otherhand, Rab5 promotes focal adhesion disassembly and modulates downstream pathways of integrin signaling,involving proteins such as Ras and Rho family GTPases. In this context, identification of upstream regulatorsand downstream effectors of Rab5, and their study represents a big challenge in order to understand howcancer cells depend on endosome control, in order to acquire more aggressive traits that lead to metastaticdisease.

Caspase-8 as a Regulator of Tumor Cell Motility by R.P. Graf, N. Keller, S. Barbero, D. Stupack (246-254).
The caspases are a family of ubiquitously expressed cysteine proteases best known for their roles inprogrammed cell death. However, caspases play a number of other roles in vertebrates. In the case ofcaspase-8, loss of expression is an embryonic lethal phenotype, and caspase-8 plays roles in suppressingcellular necrosis, promoting differentiation and immune signaling, regulating autophagy, and promoting cellularmigration. Apoptosis and migration require localization of caspase-8 in the periphery of the cells, wherecaspase-8 acts as part of distinct biosensory complexes that either promote migration in appropriate cellularmicroenvironments, or cell death in inappropriate settings. In the cellular periphery, caspase-8 interacts withcomponents of the focal adhesion complex in a tyrosine-kinase dependent manner, promoting both cellmigration in vitro and metastasis in vivo. Mechanistically, caspase-8 interacts with components of both focaladhesions and early endosomes, enhancing focal adhesion turnover and promoting rapid integrin recycling tothe cell surface. Clinically, this suggests that the expression of caspase-8 may not always be a positiveprognostic sign, and that the role of caspase-8 in cancer progression is likely context-dependent.

Caveolin-1 in Cell Migration and Metastasis by S. Nunez-Wehinger, R.J. Ortiz, N. Diaz, J. Diaz, L. Lobos-Gonzalez, A.F.G. Quest (255-274).
Caveolin-1 is a member of the caveolin family that has been ascribed a dual role in cancer. In earlystages of disease the protein functions predominantly as a tumor suppressor, whereas at later stages,caveolin-1 expression is associated with tumor progression and metastasis. Here, some mechanismsassociated with caveolin-1-dependent tumor suppression will be briefly discussed before focusing on the roleof this protein and particularly phosphorylation of tyrosine-14 in promoting cell migration, invasion andmetastasis. Models are provided summarizing possible explanations for these dramatic changes in function, aswell as mechanisms by which this may be achieved.

Signaling Pathways Involved in Neuron-Astrocyte Adhesion and Migration by A. Cardenas, M. Kong, A. Alvarez, H. Maldonado, L. Leyton (275-290).
Astrocytes in the normal brain possess a stellate shape reflecting their non-migratory properties.Alternatively, in neurodegenerative diseases or after injury, astrocytes become “reactive” in a process knownas astrocytosis or reactive gliosis, retract their processes, become polarized and acquire front-to-rearasymmetry typical of migratory cells. On the other hand, neuronal migration is a common process duringembryonic development, but only few types of neurons can migrate and differentiate during adult life in thecentral nervous system. Those that do migrate follow tracks made by glial cells and mainly give rise tointerneurons. In vitro, molecular mechanisms involved in adhesion of cells to and migration on extracellularmatrix proteins have been widely studied; however, signal transduction pathways explaining how particularlyneurons and astrocytes, mutually modulate adhesion and migration are less well known. In this review, wedescribe and discuss how ligand/receptor interactions in astrocytes and neurons trigger signaling eventsleading to actin and microtubule reorganization, changes in cell morphology, as well as cell adhesion andmigration. The biological significance these cell-cell interactions and signaling events might have in the brainare discussed.

Computational Methods for Analysis of Dynamic Events in Cell Migration by V. Castaneda, M. Cerda, F. Santibanez, J. Jara, E. Pulgar, K. Palma, C.G. Lemus, M. Osorio-Reich, M.L. Concha, S. Hartel (291-307).
Cell migration is a complex biological process that involves changes in shape and organization atthe sub-cellular, cellular, and supra-cellular levels. Individual and collective cell migration can be assessed invitro and in vivo starting from the flagellar driven movement of single sperm cells or bacteria, bacterial glidingand swarming, and amoeboid movement to the orchestrated movement of collective cell migration. One keytechnology to access migration phenomena is the combination of optical microscopy with image processingalgorithms. This approach resolves simple motion estimation (e.g. preferred direction of migrating cells or pathcharacteristics), but can also reveal more complex descriptors (e.g. protrusions or cellular deformations). Inorder to ensure an accurate quantification, the phenomena under study, their complexity, and the requiredlevel of description need to be addressed by an adequate experimental setup and processing pipeline. Here,we review typical workflows for processing starting with image acquisition, restoration (noise and artifactremoval, signal enhancement), registration, analysis (object detection, segmentation and characterization) andinterpretation (high level understanding). Image processing approaches for quantitative description of cellmigration in 2- and 3-dimensional image series, including registration, segmentation, shape and topologydescription, tracking and motion fields are presented. We discuss advantages, limitations and suitability fordifferent approaches and levels of description.