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1.  To phosphorylate or not to phosphorylate 
Cell Adhesion & Migration  2013;8(1):1-4.
EphB tyrosine kinase receptors have been implicated in multiple developmental processes; however, the signaling mechanism underlying these events remains unclear. Through a triple knock-in mouse line for three neurally expressed EphBs, Sokis et al. demonstrated that EphB tyrosine kinase activity is required for axon guidance but does not influence synapse formation. This short communication highlights their study and appealing molecular approach that elucidated the functions of EphB tyrosine kinase during developmental events.
doi:10.4161/cam.27478
PMCID: PMC3974787  PMID: 24589619
Eph B; ephrin; tyrosine kinase; bidirectional signaling; PP1 analogue
2.  Phosphorylation-mediated regulation of GEFs for RhoA 
Cell Adhesion & Migration  2013;8(1):11-18.
Spatio-temporal control of RhoA GTPase is critical for regulation of cell migration, attachment to extracellular matrix, and cell–cell adhesions. Activation of RhoA is mediated by guanine nucleotide exchange factors (GEFs), a diverse family of enzymes that are controlled by multiple signaling pathways regulating actin cytoskeleton and cell migration. GEFs can be regulated by different mechanisms. Growing evidence demonstrates that phosphorylation serves as one of the predominant signals controlling activity, interactions, and localization of RhoGEFs. It acts as a positive and a negative regulator, and allows for regulation of RhoGEFs by multiple signaling cascades. Although there are common trends in phosphorylation-mediated regulation of some RhoGEF homologs, the majority of GEFs utilize distinct mechanisms that are dictated by their unique structure and interaction networks. This diversity enables multiple signaling pathways to use different RhoGEFs for regulation of a single central—RhoA. Here, we review current examples of phosphorylation-mediated regulation of GEFs for RhoA and its role in cell migration, discuss mechanisms, and provide insights into potential future directions.
doi:10.4161/cam.28058
PMCID: PMC3974788  PMID: 24589508
RhoA; RhoGEF; phosphorylation; kinase; cell migration
3.  Palladin regulation of the actin structures needed for cancer invasion 
Cell Adhesion & Migration  2013;8(1):29-35.
Cell migration and invasion involve the formation of cell adhesion structures as well as the dynamic and spatial regulation of the cytoskeleton. The adhesive structures known as podosomes and invadopodia share a common role in cell motility, adhesion, and invasion, and form when the plasma membrane of motile cells undergoes highly regulated protrusions. Palladin, a molecular scaffold, co-localizes with actin-rich structures where it plays a role in their assembly and maintenance in a wide variety of cell lines. Palladin regulates actin cytoskeleton organization as well as cell adhesion formation. Moreover, palladin contributes to the invasive nature of cancer metastatic cells by regulating invadopodia formation. Palladin seems to regulate podosome and invodopodia formation through Rho GTPases, which are known as key players in coordinating the cellular responses required for cell migration and metastasis.
doi:10.4161/cam.28024
PMCID: PMC3974790  PMID: 24525547
Palladin; actin; invasion; invadopodia; podosome
4.  Cell penetration to nanofibrous scaffolds 
Cell Adhesion & Migration  2013;8(1):36-41.
Cell infiltration is a critical parameter for the successful development of 3D matrices for tissue engineering. Application of electrospun nanofibers in tissue engineering has recently attracted much attention. Notwithstanding several of their advantages, small pore size and small thickness of the electrospun layer limit their application for development of 3D scaffolds. Several methods for the pore size and/or electrospun layer thickness increase have been recently developed. Nevertheless, tissue engineering still needs emerging of either novel nanofiber-enriched composites or new techniques for 3D nanofiber fabrication. Forcespinning® seems to be a promising alternative. The potential of the Forcespinning® method is illustrated in preliminary experiment with mesenchymal stem cells.
doi:10.4161/cam.27477
PMCID: PMC3974791  PMID: 24429388
Forcespinning®; cell penetration; electrospinning; fibrous scaffold; mesenchymal stem cells
5.  Emerging role for nuclear rotation and orientation in cell migration 
Cell Adhesion & Migration  2013;8(1):42-48.
Nucleus movement, positioning, and orientation is precisely specified and actively regulated within cells, and it plays a critical role in many cellular and developmental processes. Mutation of proteins that regulate the nucleus anchoring and movement lead to diverse pathologies, laminopathies in particular, suggesting that the nucleus correct positioning and movement is essential for proper cellular function. In motile cells that polarize toward the direction of migration, the nucleus undergoes controlled rotation promoting the alignment of the nucleus with the axis of migration. Such spatial organization of the cell appears to be optimal for the cell migration. Nuclear reorientation requires the cytoskeleton to be anchored to the nuclear envelope, which exerts pulling or pushing torque on the nucleus. Here we discuss the possible molecular mechanisms regulating the nuclear rotation and reorientation and the significance of this type of nuclear movement for cell migration.
doi:10.4161/cam.27761
PMCID: PMC3974792  PMID: 24589621
cell polarity; migration; nuclear reorientation; LINC; actin; microtubules; focal adhesions; FAK; dynein; myosin
6.  Semaphorin 3A 
Cell Adhesion & Migration  2013;8(1):5-10.
Semaphorin 3A (Sema3A) is a protein identified originally as a diffusible axonal chemorepellent. Sema3A has multifunctional roles in embryonic development, immune regulation, vascularization, and oncogenesis. Bone remodeling consists of two phases: the removal of mineralized bone by osteoclasts and the formation of new bone by osteoblasts, and plays an essential role in skeletal diseases such as osteoporosis. Recent studies have shown that Sema3A is implicated in the regulation of osteoblastgenesis and osteoclastgenesis. Moreover, low bone mass in mice with specific knockout of Sema3A in the neurons indicates that Sema3A regulates bone remodeling indirectly. This review highlights recent advances on our understanding of the role of sema3A as a new player in the regulation of bone remodeling and proposes the potential of sema3A in the diagnosis and therapy of bone diseases.
doi:10.4161/cam.27752
PMCID: PMC3974794  PMID: 24589620
Semaphorin 3A; bone remodeling; sensory innervation; osteoclast; osteoblast
7.  Mammalian CAP (Cyclase-associated protein) in the world of cell migration 
Cell Adhesion & Migration  2013;8(1):55-59.
Cell migration is essential for a variety of fundamental biological processes such as embryonic development, wound healing, and immune response. Aberrant cell migration also underlies pathological conditions such as cancer metastasis, in which morphological transformation promotes spreading of cancer to new sites. Cell migration is driven by actin dynamics, which is the repeated cycling of monomeric actin (G-actin) into and out of filamentous actin (F-actin). CAP (Cyclase-associated protein, also called Srv2) is a conserved actin-regulatory protein, which is implicated in cell motility and the invasiveness of human cancers. It cooperates with another actin regulatory protein, cofilin, to accelerate actin dynamics. Hence, knockdown of CAP1 slows down actin filament turnover, which in most cells leads to reduced cell motility. However, depletion of CAP1 in HeLa cells, while causing reduction in dynamics, actually led to increased cell motility. The increases in motility are likely through activation of cell adhesion signals through an inside-out signaling. The potential to activate adhesion signaling competes with the negative effect of CAP1 depletion on actin dynamics, which would reduce cell migration. In this commentary, we provide a brief overview of the roles of mammalian CAP1 in cell migration, and highlight a likely mechanism underlying the activation of cell adhesion signaling and elevated motility caused by depletion of CAP1.
doi:10.4161/cam.27479
PMCID: PMC3974795  PMID: 24429384
actin cytoskeleton; cell migration; cofilin; cell adhesion; FAK; Talin; srv2
8.  Recombinant disintegrin targets α(v) β(3) integrin and leads to mediator production 
Cell Adhesion & Migration  2013;8(1):60-65.
Integrin αvβ3 is most likely the foremost modulator of angiogenesis among all known integrins. Recombinant disintegrin DisBa-01, originally obtained from snake venom glands, binds to αvβ3, thereby significantly inhibiting adhesion and generating in vivo anti-metastatic ability. However, its function in mediator production is not clear. Here, we observed that the mediators VEGF-A, IL-8, and TGF-β are not produced by human umbilical vein endothelial cells (HUVEC cell line) or monocyte/macrophage cells (SC cell line) when cells adhered to vitronectin. However, when exposed to DisBa-01, HUVECs produced higher levels of TGF-β, and SC cells produced higher levels of VEGF-A. Nonetheless, HUVECs also showed an enhancement of apoptosis after losing adherence when exposed to disintegrin, which is a characteristic of anoikis. We propose that disintegrin DisBa-01 could be used to modulate integrin αvβ3 functions.
doi:10.4161/cam.27698
PMCID: PMC3974796  PMID: 24589623
DisBa; HUVEC; IL-8; TGF; VEGF; cancer; endothelial cell; integrin αvβ3; macrophage
9.  Neutrophil integrin affinity regulation in adhesion, migration, and bacterial clearance 
Cell Adhesion & Migration  2013;7(6):476-481.
During an infection, neutrophils are the first immune cells to arrive armed to clear the invading pathogen. In order to do so, neutrophils need to transmigrate from the peripheral blood through the endothelial layer toward the site of inflammation. This process is in most cases dependent on integrins, adhesion molecules present on all immune cells. These molecules are functionally regulated by “inside-out” signaling, where stimulus-induced signaling pathways act on the intracellular integrin tail to regulate the activity of the receptor on the outside. Both a change in conformation (affinity) and clustering (avidity/valency) of the receptors occurs and many factors have been linked to regulation of integrins on neutrophils. Control of integrin conformation and clustering is of pivotal importance for proper cell adhesion, migration, and bacterial clearance. Recently, gelsolin was found to be involved in β1-integrin affinity regulation and cell adhesion. Here, I summarize the role of neutrophil integrin regulation in the essential steps to reach the site of inflammation and clearance of bacterial pathogens.
doi:10.4161/cam.27293
PMCID: PMC3916351  PMID: 24430200
integrin; gelsolin; adhesion; migration; phagocytosis; neutrophil; reverse migration
10.  Rac1 mediates laminar shear stress-induced vascular endothelial cell migration 
Cell Adhesion & Migration  2013;7(6):462-468.
The migration of endothelial cells (ECs) plays an important role in vascular remodeling and regeneration. ECs are constantly subjected to shear stress resulting from blood flow and are able to convert mechanical stimuli into intracellular signals that affect cellular behaviors and functions. The aim of this study is to elucidate the effects of Rac1, which is the member of small G protein family, on EC migration under different laminar shear stress (5.56, 10.02, and 15.27 dyn/cm2). The cell migration distance under laminar shear stress increased significantly than that under the static culture condition. Especially, under relative high shear stress (15.27 dyn/cm2) there was a higher difference at 8 h (P < 0.01) and 2 h (P < 0.05) compared with static controls. RT-PCR results further showed increasing mRNA expression of Rac1 in ECs exposed to laminar shear stress than that exposed to static culture. Using plasmids encoding the wild-type (WT), an activated mutant (Q61L), and a dominant-negative mutant (T17N), plasmids encoding Rac1 were transfected into EA.hy 926 cells. The average net migration distance of Rac1Q61L group increased significantly, while Rac1T17N group decreased significantly in comparison with the static controls. These results indicated that Rac1 mediated shear stress-induced EC migration. Our findings conduce to elucidate the molecular mechanisms of EC migration induced by shear stress, which is expected to understand the pathophysiological basis of wound healing in health and diseases.
doi:10.4161/cam.27171
PMCID: PMC3916349  PMID: 24430179
Rac1; shear stress; endothelial cell migration
11.  The neurite growth inhibitory protein Nogo-A has diverse roles in adhesion and migration 
Cell Adhesion & Migration  2013;7(6):451-454.
doi:10.4161/cam.27164
PMCID: PMC3916347  PMID: 24401759
Nogo-A; migration; adhesion; proliferation; cerebellum
12.  Endothelial permeability and VE-cadherin 
Cell Adhesion & Migration  2013;7(6):455-461.
The endothelium forms a selective semi-permeable barrier controlling bidirectional transfer between blood vessel and irrigated tissues. This crucial function relies on the dynamic architecture of endothelial cell–cell junctions, and in particular, VE-cadherin-mediated contacts. VE-cadherin indeed chiefly organizes the opening and closing of the endothelial barrier, and is central in permeability changes. In this review, the way VE-cadherin-based contacts are formed and maintained is first presented, including molecular traits of its expression, partners, and signaling. In a second part, the mechanisms by which VE-cadherin adhesion can be disrupted, leading to cell–cell junction weakening and endothelial permeability increase, are described. Overall, the molecular basis for VE-cadherin control of the endothelial barrier function is of high interest for biomedical research, as vascular leakage is observed in many pathological conditions and human diseases.
doi:10.4161/cam.27330
PMCID: PMC3916348  PMID: 24430214
VE-cadherin; permeability; VEGF; catenins; internalization; phosphorylation; vascular barrier; endothelial cells
13.  How does cancer cell metabolism affect tumor migration and invasion? 
Cell Adhesion & Migration  2013;7(5):395-403.
Cancer metastasis is the major cause of cancer-associated death. Accordingly, identification of the regulatory mechanisms that control whether or not tumor cells become “directed walkers” is a crucial issue of cancer research. The deregulation of cell migration during cancer progression determines the capacity of tumor cells to escape from the primary tumors and invade adjacent tissues to finally form metastases. The ability to switch from a predominantly oxidative metabolism to glycolysis and the production of lactate even when oxygen is plentiful is a key characteristic of cancer cells. This metabolic switch, known as the Warburg effect, was first described in 1920s, and affected not only tumor cell growth but also tumor cell migration. In this review, we will focus on the recent studies on how cancer cell metabolism affects tumor cell migration and invasion. Understanding the new aspects on molecular mechanisms and signaling pathways controlling tumor cell migration is critical for development of therapeutic strategies for cancer patients.
doi:10.4161/cam.26345
PMCID: PMC3903682  PMID: 24131935
cancer cell metabolism; cell migration; metastasis; glycolysis; glutamine
14.  Role of the AP-1 transcription factor FOSL1 in endothelial cells adhesion and migration 
Cell Adhesion & Migration  2013;7(5):408-411.
Vasculogenesis and angiogenesis, the fundamental processes by which new blood vessels are formed, involve the proliferation, migration, and remodeling of endothelial cells. Dynamic adhesion of endothelial cells to extracellular matrix plays a fundamental role in all these events. Key regulators of endothelial cells adhesion and migration are the αvβ3 and uPA-uPAR complexes. The αvβ3 integrin heterodimer is the receptor for extracellular matrix components such as vitronectin and is overexpressed on the cell surface of angiogenic endothelial cells, but not quiescent cells lining normal vessels. The uPA-uPAR complex contributes to extracellular matrix remodeling by mediating proteolytic activity at the leading edge of migrating cells. We recently reported that the FOSL1 transcription factor of the AP-1 family plays a pivotal role in the regulation of the level of the αvβ3 and uPA-uPAR complexes on the surface of endothelial cells. In this commentary, we review the current knowledge of αv and β3 transcriptional regulation in endothelial cells and discuss the role of FOSL1 in angiogenesis.
doi:10.4161/cam.25894
PMCID: PMC3903684  PMID: 24084233
AP-1; Angiogenesis; FOSL1; FRA1; SP1; endothelial cell migration; transcription; uPA; uPAR; αvβ3 integrin
15.  Transglutaminase-2 in cell adhesion 
Cell Adhesion & Migration  2013;7(5):412-417.
Cell-matrix adhesion is a fundamental biological process that governs survival, migration, and proliferation of living eukaryotic cells. Paxillin is an important central player in a network of adhesome proteins that form focal adhesion complexes. Phosphorylation of tyrosine and serine residues in paxillin is critical for the coordinated sequential recruitment of other adaptor and kinase proteins to adhesion complexes. Recently, the phosphorylation of serine178 in paxillin has been shown to be vital for epithelial cell adhesion and migration. In vivo and in vitro evidence have shown that transglutaminase (TG)-2 positively regulates this phosphorylation. Here, we propose three possible mechanisms that may explain these observations. First, TG-2 itself may be an adhesome member directly interacting with paxillin in a non-covalent way. Second, TG-2 may cross link a mitogen-activated protein kinase kinase kinase (MAP3K), which eventually activates c-Jun N-terminal kinase (JNK), and the latter phosphorylates paxillin. Lastly, TG-2 may have intrinsic kinase activity that phosphorylates paxillin. Future studies investigating these hypotheses on TG-2-paxillin relationships are necessary in order to address this fundamental process in cell matrix adhesion signaling.
doi:10.4161/cam.26344
PMCID: PMC3903685  PMID: 24193434
adhesion; signaling; paxillin; migration; transglutaminase; adhesome; review; cell culture
16.  Epithelial-mesenchymal transition and its regulators are major targets of triple-negative breast cancer 
Cell Adhesion & Migration  2013;7(5):424-425.
Triple negative breast cancers (TNBCs) represent a distinct subtype of breast cancers that are associated with early recurrence and an aggressive metastatic progression of the disease and consequently poor outcome. Recently, it was reported that c-Met growth factor receptor is overexpressed in around 52% of TNBCs. On the other hand, it is known that c-Met signaling pathways initiate the epithelial–mesenchymal transition (EMT) phenomenon, which is described as a crucial event during cancer metastasis. Herein, we discuss the association between c-Met and EMT in the TNBC group.
doi:10.4161/cam.26728
PMCID: PMC3903687  PMID: 24152786
EMT; c-Met; IGF-1; Leptin; triple negative; breast cancer; metastasis & cancer mortality
17.  Regulation of cell shape and adhesion by CD34 
Cell Adhesion & Migration  2013;7(5):426-433.
We previously reported that expression of CD43/leukosialin induces cell rounding and microvillus formation via inhibition of cell adhesion. Here, we found that CD34, a cell surface sialomucin and marker for hematopoietic progenitor cells, also inhibited cell adhesion and induced cell rounding and microvillus formation. Forced expression of CD34-induced cell rounding, microvillus formation, and phosphorylation of ezrin/radixin/moesin (ERM) proteins in HEK293T cells, while inhibiting integrin-mediated cell re-attachment. Furthermore, CD34+ blood cells and KG-1 cells, which express endogenous CD34 on their surface, were spherical in shape, surrounded by microvilli, and non-adherent to substrata. In addition, cleavage of O-sialomucin augmented integrin-mediated cell adhesion of KG-1 cells. These results suggest the involvement of CD34 in the inhibition of integrin-mediated cell adhesion and formation of the cell surface structure. The inhibitory function of CD34 in cell adhesion may affect cell shape organization via phosphorylation of ERM proteins. Cellular structures such as the spherical shape and microvilli of CD34+ cells may also contribute to regulation of cell adhesion.
doi:10.4161/cam.25957
PMCID: PMC3903688  PMID: 24036614
CD34; ERM proteins; cell adhesion; cell rounding; microvilli; phosphorylation; sialomucin
18.  Shape in migration 
Cell Adhesion & Migration  2013;7(5):450-459.
Unsuccessful cytotoxic anticancer treatments may contribute to tumor morphologic instability and consequent tissue invasion, promoting the selection of a more malignant phenotype. Indeed, morphological changes have been demonstrated to be more pronounced in strongly vs. weakly metastatic cells.
By means of normalized bending energy, we have previously quantitatively defined the link between cell shape modifications and the acquisition of a more malignant phenotype by 5-FU-resistant colon cancer cells (HCT-8FUres). Such changes were significantly correlated with an increase in motility speed. Herein, we propose a method to quantitatively analyze the shape of wild and chemoresistant HCT-8 migration front cells during wound healing assay. We evaluated the reliability of parameters (area/perimeter ratio [A/p], circularity, roundness, fractal dimension, and solidity) in describing the biological behavior of the two cell lines, enabling hence in distinguishing the chemoresistant line from the other one. We found solidity index the parameter that better described the difference between chemoresistant and wild cells. Moreover, solidity is able to capture the differences between chemoresistant and wild cells at each time point of the migration process. Indeed, motility speed was found to be inversely correlated with solidity, a quantitative index of cell deformability. Deformability is an outstanding hallmark of the process leading to metastatic spread; consequently, solidity may be considered a marker of acquired metastatic property.
doi:10.4161/cam.26765
PMCID: PMC3903690  PMID: 24176801
solidity; wound healing assay; cell shape; chemoresistance; metastasis; deformability
19.  Timing is everything 
Cell Adhesion & Migration  2013;7(4):351-356.
Cell adhesion to the extracellular matrix elicits a temporal reorganization of the actin cytoskeleton that is regulated first by Rac1 and later by RhoA. The signaling mechanisms controlling late stage RhoA activation are incompletely understood. Net1A is a RhoA/RhoB-specific guanine nucleotide exchange factor that is required for cancer cell motility. The ability of Net1A to stimulate RhoA activation is negatively regulated by nuclear sequestration. However, mechanisms controlling the plasma membrane localization of Net1A had not previously been reported. Recently we have shown that Rac1 activation stimulates plasma membrane relocalization and activation of Net1A. Net1A relocalization is independent of its catalytic activity and does not require its C-terminal pleckstrin homology or PDZ interacting domains. Rac1 activation during cell adhesion stimulates a transient relocalization of Net1A that is terminated by proteasomal degradation of Net1A. Importantly, plasma membrane localization of Net1A is required for efficient myosin light chain phosphorylation, focal adhesion maturation, and cell spreading. These data show for the first time a physiological mechanism controlling Net1A relocalization from the nucleus. They also demonstrate a previously unrecognized role for Net1A in controlling actomyosin contractility and focal adhesion dynamics during cell adhesion.
doi:10.4161/cam.25276
PMCID: PMC3739811  PMID: 23792411
Rac1; RhoA; Net1A; cell adhesion; focal adhesion; breast cancer
20.  Par6 is phosphorylated by aPKC to facilitate EMT 
Cell Adhesion & Migration  2013;7(4):357-361.
The conserved polarity proteins Par6 and aPKC regulate cell polarization processes. However, increasing evidence also suggests that they play a role in oncogenic progression. During tumor progression, epithelial to mesenchymal transition (EMT) delineates an evolutionary conserved process that converts stationary epithelial cells into mesenchymal cells, which have an acquired ability for independent migration and invasion. In addition to signaling pathways that alter genetic programes that trigger the loss of cell-cell adhesion, alternative pathways can alter cell plasticity to regulate cell-cell cohesion and increase invasive potential. One such pathway involves TGFβ-induced phosphorylation of Par6. In epithelial cells, Par6 phosphorylation results in the dissolution of junctional complexes, cytoskeletal remodelling, and increased metastatic potential. Recently, we found that aPKC can also phosphorylate Par6 to drive EMT and increase the migratory potential of non-small cell lung cancer cells. This result has implications with respect to homeostatic and developmental processes involving polarization, and also with respect to cancer progression—particularly since aPKC has been reported to be an oncogenic regulator in various tumor cells.
doi:10.4161/cam.25651
PMCID: PMC3739812  PMID: 23880940
EMT; Par3; Par6; RhoA; Smurf1; TGFβ; aPKC; cell polarity
21.  Src-inducible association of CrkL with procaspase-8 promotes cell migration 
Cell Adhesion & Migration  2013;7(4):362-369.
Procaspase-8, the zymogen form of the apoptosis-initiator caspase-8, undergoes phosphorylation following integrin-mediated cell attachment to an extracellular matrix substrate. Concordant with cell attachment to fibronectin, a population of procaspase-8 becomes associated with a peripheral insoluble compartment that includes focal complexes and lamellar microfilaments. Phosphorylation of procaspase-8 both impairs its maturation to the proapoptotic form and can promote cell migration. Here we show that the cytoskeletal adaptor protein CrkL promotes caspase-8 recruitment to the peripheral spreading edge of cells, and that the catalytic domain of caspase-8 directly interacts with the SH2 domain of CrkL. We show that the interaction is abolished by shRNA-mediated silencing of Src, in Src-deficient MEFs, and by pharmacologic inhibitors of the kinase. The results provide insight into how tyrosine kinases may act to coordinate the suppression caspase-8 mediated apoptosis, while promoting cell invasion.
doi:10.4161/cam.25284
PMCID: PMC3739813  PMID: 23751956
caspase 8; Crk-L; Crk; Src; FAK; phosphorylation
22.  Abnormal myelination in the spinal cord of PTPα-knockout mice 
Cell Adhesion & Migration  2013;7(4):370-376.
PTPα interacts with F3/contactin to form a membrane-spanning co-receptor complex to transduce extracellular signals to Fyn tyrosine kinase. As both F3 and Fyn regulate myelination, we investigated a role for PTPα in this process. Here, we report that both oligodendrocytes and neurons express PTPα that evenly distributes along myelinated axons of the spinal cord. The ablation of PTPα in vivo leads to early formation of transverse bands that are mainly constituted by F3 and Caspr along the axoglial interface. Notably, PTPα deficiency facilitates abnormal myelination and pronouncedly increases the number of non-landed oligodendrocyte loops at shortened paranodes in the spinal cord. Small axons, which are normally less myelinated, have thick myelin sheaths in the spinal cord of PTPα-null animals. Thus, PTPα may be involved in the formation of axoglial junctions and ensheathment in small axons during myelination of the spinal cord.
doi:10.4161/cam.25652
PMCID: PMC3739814  PMID: 23934023
Axon; Caspr; F3/contactin; Myelination; PTPα
23.  The actin cytoskeleton in presynaptic assembly 
Cell Adhesion & Migration  2013;7(4):379-387.
Dramatic morphogenetic processes underpin nearly every step of nervous system development, from initial neuronal migration and axon guidance to synaptogenesis. Underlying this morphogenesis are dynamic rearrangements of cytoskeletal architecture. Here we discuss the roles of the actin cytoskeleton in the development of presynaptic terminals, from the elaboration of terminal arbors to the recruitment of presynaptic vesicles and active zone components. The studies discussed here underscore the importance of actin regulation at every step in neuronal circuit assembly.
doi:10.4161/cam.24803
PMCID: PMC3739815  PMID: 23628914
actin; active zone; synapse; synaptic adhesion; synaptic vesicle clustering; terminal arborization
24.  Mesenchymal stem cell-derived CCL-9 and CCL-5 promote mammary tumor cell invasion and the activation of matrix metalloproteinases 
Cell Adhesion & Migration  2013;7(3):315-324.
Stromal chemokine gradients within the breast tissue microenvironment play a critical role in breast cancer cell invasion, a prerequisite to metastasis. To elucidate which chemokines and mechanisms are involved in mammary cell migration we determined whether mesenchymal D1 stem cells secreted specific chemokines that differentially promoted the invasion of mammary tumor cells in vitro. Results indicate that mesenchymal D1 cells produced concentrations of CCL5 and CCL9 4- to 5-fold higher than the concentrations secreted by 4T1 tumor cells (P < 0.01). Moreover, 4T1 tumor cell invasion toward D1 mesenchymal stem cell conditioned media (D1CM), CCL5 alone, CCL9 alone or a combination CCL5 and CCL9 was observed. The invasion of 4T1 cells toward D1 mesenchymal stem CM was dose-dependently suppressed by pre-incubation with the CCR1/CCR5 antagonist met-CCL5 (P < 0.01). Furthermore, the invasion of 4T1 cells toward these chemokines was prevented by incubation with the broad-spectrum MMP inhibitor GM6001. Additionally, the addition of specific MMP9/MMP13 and MMP14 inhibitors prevented the MMP activities of supernatants collected from 4T1 cells incubated with D1CM, CCL5 or CCL9. Taken together these data highlight the role of CCL5 and CCL9 produced by mesenchymal stem cells in mammary tumor cell invasion.
doi:10.4161/cam.25138
PMCID: PMC3711999  PMID: 23722213
chemokine; chemokine receptor; cell migration; breast tumor; mesenchymal stem cell; MMPs
25.  α6 integrin subunit regulates cerebellar development 
Cell Adhesion & Migration  2013;7(3):325-332.
Mutations in genes encoding several basal lamina components as well as their cellular receptors disrupt normal deposition and remodeling of the cortical basement membrane resulting in a disorganized cerebral and cerebellar cortex. The α6 integrin was the first α subunit associated with cortical lamination defects and formation of neural ectopias. In order to understand the precise role of α6 integrin in the central nervous system (CNS), we have generated mutant mice carrying specific deletion of α6 integrin in neuronal and glia precursors by crossing α6 conditional knockout mice with Nestin-Cre line. Cerebral cortex development occurred properly in the resulting α6fl/fl;nestin-Cre mutant animals. Interestingly, however, cerebellum displayed foliation pattern defects although granule cell (GC) proliferation and migration were not affected. Intriguingly, analysis of Bergmann glial (BG) scaffold revealed abnormalities in fibers morphology associated with reduced processes outgrowth and altered actin cytoskeleton. Overall, these data show that α6 integrin receptors are required in BG cells to provide a proper fissure formation during cerebellum morphogenesis.
doi:10.4161/cam.25140
PMCID: PMC3712000  PMID: 23722246
integrin; laminin; cerebellum; Bergmann glial cell; cerebellar foliation

Results 1-25 (488)