SwePub - search: WFRF:(Aspenström Pontus)

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1.	Aspenström-Fagerlund, Bitte, et al. (author) Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes 2007 In: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 237:1-3, s. 12-23 Journal article (peer-reviewed)abstract Surface active compounds present in food possibly have the ability to enhance the absorption of water soluble toxic agents. Therefore, we investigated whether fatty acids such as oleic acid and docosahexaenoic acid (DHA), both commonly present in food, negatively affect the integrity of tight junctions (TJ) in the intestinal epithelium and thereby increase the absorption of poorly absorbed hydrophilic substances. Caco-2 cells, which are derived from human absorptive enterocytes, were grown on permeable filters for 20-25 days. Differentiated cell monolayers were apically exposed for 90min to mannitol in emulsions of oleic acid (5, 15 or 30mM) or DHA (5, 15 or 30mM) in an experimental medium with or without Ca(2+) and Mg(2+). Absorption of (14)C-mannitol increased and trans-epithelial electrical resistance (TEER) decreased in cell monolayers exposed to oleic acid and DHA, compared to controls. Cytotoxicity, measured as leakage of LDH, was higher in groups exposed to 30mM oleic acid and all concentrations of DHA. Morphology of the cell monolayers was studied by using fluorescence microscopy. Exposure of cell monolayers to 5mM DHA for 90min resulted in a profound alteration of the cell-cell contacts as detected by staining the cells for beta-catenin. Oleic acid (30mM) treatment also induced dissolution of the cell-cell contacts but the effect was not as pronounced as with DHA. Cell monolayers were also exposed for 180min to 250nM cadmium (Cd) in emulsions of oleic acid (5 or 30mM) or DHA (1 or 5mM), in an experimental medium with Ca(2+) and Mg(2+). Retention of Cd in Caco-2 cells was higher after exposure to 5mM oleic acid but lower after exposure to 30mM oleic acid and DHA. Absorption of Cd through the monolayers increased after DHA exposure but not after exposure to oleic acid. Our results indicate that fatty acids may compromise the integrity of the intestinal epithelium and that certain lipids in food may enhance the paracellular absorption of poorly absorbed hydrophilic substances.
2.	Aase, Karin, et al. (author) Angiomotin regulates endothelial cell migration during embryonic angiogenesis 2007 In: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:16, s. 2055-2068 Journal article (peer-reviewed)abstract The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.
3.	Aspenström, Pontus, et al. (author) Pombe Cdc15 homology proteins : regulators of membrane dynamics and the actin cytoskeleton 2006 In: TIBS -Trends in Biochemical Sciences. Regular ed.. - : Elsevier BV. - 0968-0004 .- 1362-4326. ; 31:12, s. 670-679 Research review (peer-reviewed)abstract Pombe Cdc15 homology (PCH) proteins have emerged in many species as important coordinators of signalling pathways that regulate actomyosin assembly and membrane dynamics. For example, the prototype PCH protein, Cdc15p of Schizosaccharomyces pombe, has a role in assembly of the contractile ring, which is needed to separate dividing cells. Recently, mammalian PCH proteins have been found to bind phospholipids and to participate in membrane deformation. These findings suggest that PCH proteins are crucial linkers of membrane dynamics and actin polymerization, for example, during the internalization of transmembrane receptors. Intriguingly, some members of the PCH protein family are mutated in neurodegenerative and inflammatory diseases, which has implications for the identification of cures for such disorders.
4.	Aspenström, Pontus (author) Roles of F-BAR/PCH Proteins in the Regulation of Membrane Dynamics and Actin Reorganization 2009 In: International Review of Cell and Molecular Biology. ; 272, s. 1-31 Research review (peer-reviewed)abstract The Pombe Cdc15 Homology (PCH) proteins have emerged in many species as important coordinators of signaling pathways that regulate actomyosin assembly and membrane dynamics. The hallmark of the PCH proteins is the presence of a Fes/ClP4 homology-Bin/Amphiphysin/Rvsp (F-BAR) domain; therefore they are commonly referred to as F-BAR proteins. The prototype F-BAR protein, Cdc15p of Schizosaccharomyces pombe, has a role in the formation of the contractile actomyosin ring during cytokinesis. Vertebrate F-BAR proteins have an established role in binding phospholipids and they participate in membrane deformations, for instance, during the internalization of transmembrane receptors. This way the F-BAR proteins will function as linkers between the actin polymerization apparatus and the machinery regulating membrane dynamics. Interestingly, some members of the F-BAR proteins are implicated in inflammatory or neurodegenerative disorders and the observations can be expected to have clinical implications for the treatment of the diseases.
5.	Aspenström, Pontus, et al. (author) Taking Rho GTPases to the next level : the cellular functions of atypical Rho GTPases 2007 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 313:17, s. 3673-3679 Research review (peer-reviewed)abstract The Rho GTPases are influential regulators of signalling pathways that control vital cellular processes such as cytoskeletal dynamics, gene transcription, cell cycle progression and cell transformation. A vast majority of the studies involving Rho GTPases have been focused to the famous triad, Cdc42, Rac1 and RhoA, but this protein family actually harbours 20 members. Recently, the less known Rho GTPases have received increased attention. Many of the less studied Rho GTPases have structural, as well as, functional features which makes it pertinent to classify them as atypical Rho GTPases. This review article will focus on the critical aspects of the atypical Rho GTPases, RhoH, Wrch-1, Chp and RhoBTB. These proteins are involved in a broad spectre of biological processes, such as cytoskeletal dynamics, T-cell signalling and protein ubiquitinylation. We will also discuss the roles of atypical Rho GTPases as oncogenes or tumour suppressors, as well as their potential involvement in human diseases.
6.	Aspenström, Pontus, et al. (author) The diaphanous-related formin DAAM1 collaborates with the Rho GTPases RhoA and Cdc42, CIP4 and Src in regulating cell morphogenesis and actin dynamics 2006 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 312:12, s. 2180-2194 Journal article (peer-reviewed)abstract Binding partners for the Cdc42 effector CIP4 were identified by the yeast two-hybrid system, as well as by testing potential CIP4-binding proteins in coimmunoprecipitation experiments. One of the CIP4-binding proteins, DAAM1, was characterised in more detail. DAAM1 is a ubiquitously expressed member of the mammalian diaphanous-related formins, which include proteins such as mDia1 and mDia2. DAAM1 was shown to bind to the SH3 domain of CIP4 in vivo. Ectopically expressed DAAM1 localised in dotted pattern at the dorsal side of transfected cells and the protein was accumulated in the proximity to the microtubule organising centre. Moreover, ectopic expression of DAAM1 induced a marked alteration of the cell morphology, seen as rounding up of the cells, the formation of branched protrusions as well as a reduction of stress-fibres in the transfected cells. Coimmunoprecipitation experiments demonstrated that DAAM1 bound to RhoA and Cdc42 in a GTP-dependent manner. Moreover, DAAM1 was found to interact and collaborate with the non-receptor tyrosine kinase Src in the formation of branched protrusions. Taken together, our data indicate that DAAM1 communicates with Rho GTPases, CIP4 and Src in the regulation of the signalling pathways that co-ordinate the dynamics of the actin filament system.
7.	Aspenström, Pontus (author) The verprolin family of proteins : Regulators of cell morphogenesis and endocytosis 2005 In: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 579:24, s. 5253-5259 Research review (peer-reviewed)abstract The verprolin family of proteins, WIP, CR16 and WIRE/WICH, has emerged as critical regulators of cytoskeletal organisation in vertebrate cells. The founding father of the family, verprolin, was originally identified in budding yeast and later shown to be needed for actin polymerisation during polarised growth and during endocytosis. The vertebrate verprolins regulate actin dynamics either by binding directly to actin, by binding the WASP family of proteins or by binding to other actin regulating proteins. Interestingly, also the vertebrate verprolins have been implicated in endocytosis, demonstrating that most of the functional modules in this fascinating group of proteins have been conserved from yeast to man.
8.	Aspenström, Pontus (author) The verprolins as regulators of actin dynamics. 2006 In: Actin-monomer-binding proteins.. - Austin, Texas : Landes Biosciences. - 9780387464053 ; , s. 97-106 Book chapter (peer-reviewed)abstract Verprolin is an actin-binding protein first identified in budding yeast Saccharomyces cerevisiae. The yeast verprolin is needed for actin polymerisation during polarised growth and during endocytosis. In vertebrate cells, three genes encoding Verprolin orthologues have been identified: WIP, CR16 and WIRE/WICH. The mammalian verprolins have been implicated in the regulation of actin dynamics either by binding directly to actin, by binding the WASP family of proteins or by binding to other actin regulating proteins. This review article will bring up to discussion the current understanding of the mechanisms underlying verprolin-dependent mobilisation of the actin filament system.
9.	Berthold, Jessica, et al. (author) Characterization of RhoBTB-dependent Cul3 ubiquitin ligase complexes--evidence for an autoregulatory mechanism 2008 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 314:19, s. 3453-3465 Journal article (peer-reviewed)abstract RhoBTB proteins are atypical members of the Rho family of small GTPases. Two of the three RhoBTB proteins, RhoBTB1 and RhoBTB2, have been proposed as tumor suppressors and might function as adaptors of Cul3-dependent ubiquitin ligase complexes. Using yeast two-hybrid analysis and co-immunoprecipitation we show that all three RhoBTB proteins interact with Cul3. The interaction requires the N-terminal region of Cul3 and the first BTB domain of RhoBTB. RhoBTB3, the only RhoBTB with a prenylation motif, associates with vesicles that are frequently found in the vicinity of microtubules, suggesting a participation in some aspects of vesicle trafficking. We also show that RhoBTB2 and RhoBTB3 are capable of homo and heterodimerizing through the BTB domain region. The GTPase domain, which does not bind GTP, is able to interact with the BTB domain region, thus preventing proteasomal degradation of RhoBTB. This fits into a model in which an intramolecular interaction maintains RhoBTB in an inactive state, preventing the formation or the functionality of Cul3-dependent complexes. We also report a significantly decreased expression of RHOBTB and CUL3 genes in kidney and breast tumor samples and a very good correlation in the expression changes between RHOBTB and CUL3 that suggests that these genes are subject to a common inactivation mechanism in tumors.
10.	Edling, Charlotte, 1976- (author) Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells 2006 Doctoral thesis (other academic/artistic)abstract The receptor tyrosine kinase (RTK) c-Kit is expressed in hematopoietic stem and progenitor cells, mast cells and in several non-hematopoietic tissues. In the hematopoietic system c-Kit and its ligand Steel Factor (SF, aka Stem Cell Factor) are critical for proliferation, survival and differentiation. Mutations in either receptor or ligand lead to lethal anaemia, hematopoietic stem cell defects, mast cell deficiency and a series of non-hematological defects. The aims of the studies included in this thesis are to describe the signalling pathways downstream c-Kit in hematopoietic stem/progenitor cells and to further analyse the role of c-Kit signalling in fundamental biological functions. To study c-Kit signalling in the hematopoietic system we have employed hematopoietic stem cell-like cell lines which share many properties with primary hematopoietic stem cells in vitro and in vivo, including surface markers, multipotentiality, capacity for self-renewal and long term repopulation. In paper I we demonstrate that upon SF activation the RTK c-Kit is autophosphorylated and downstream signalling mediators are transiently activated. Surprisingly we find that the c-Kit mediated activation of the MAPK pathway is dependent on the activation of phosphoinositide 3-kinase (PI3K) in hematopoietic progenitor cells and that differentiation of these progenitors to mast cells results in a signalling switch where Raf activation changes from PI3K dependent to PI3K independent. We here establish that PI3K activity is required for viability and proliferation of hematopoietic progenitor cells. In paper II we studied the conventional protein kinase C (cPKC) involvement in c-Kit signalling. We observe that the cPKCs can phosphorylate c-Kit on serine 746 and that this phosphorylation negatively regulates the activation of the receptor. We demonstrate that inhibition of this negative phosphorylation results in dramatically increased protein kinase B (PKB) activation and as a consequence inhibition of cPKCs rescues cells from starvation induced apoptosis. Moreover we exhibit that the cPKCs are necessary for full activation of extracellular signal-regulated kinase (Erk) and that impaired PKC activity leads to hampered proliferation. In paper III we demonstrate that in addition to the cPKCs also the novel PKC is required for Erk activation and proliferation. Furthermore we present results indicating that PKC negatively regulates differentiation of bone marrow. In conclusion, with the studies in this thesis we display details in the signalling pathways induced upon RTK c-Kit activation and we demonstrate that c-Kit has significant effects on hematopoietic cell-physiology.
11.	Edlund, Sofia, et al. (author) Interaction between Smad7 and beta-catenin : importance for transforming growth factor beta-induced apoptosis 2005 In: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 25:4, s. 1475-1488 Journal article (peer-reviewed)abstract Members of the transforming growth factor beta (TGF-beta) and Wnt/wingless superfamilies regulate cell fate during development and tissue maintenance. Here we report that Smad7 interacts with beta-catenin and lymphoid enhancer binding factor 1/T-cell-specific factor (LEF1/TCF), transcriptional regulators in Wnt signaling, in a TGF-beta-dependent manner. Smad7 was found to be required for TGF-beta1-induced accumulation of beta-catenin and LEF1 in human prostate cancer (PC-3U) cells as well as in human keratinocytes (HaCaT cells). Moreover, when the endogenous Smad7 was repressed by specific small interfering RNA, TGF-beta-induced increase of activated p38, Akt phosphorylated on Ser473, glycogen synthase kinase 3beta phosphorylated on Ser9 was prevented, as well as the TGF-beta-induced association between beta-catenin and LEF1. Notably, the observed physical association of Smad7 and beta-catenin was found to be important for TGF-beta-induced apoptosis, since suppression of beta-catenin expression by small interfering RNA decreased the apoptotic response to TGF-beta.
12.	Fransson, Åsa, 1976- (author) Cell signaling by Rho and Miro GTPases : Studies of Rho GTPases in Cytoskeletal Reorganizations and of Miro GTPases in Mitochondrial Dynamics 2008 Doctoral thesis (other academic/artistic)abstract The Ras superfamily of GTPases embraces six major branches of proteins: the Ras, Rab, Ran, Arf, Rho and Miro subfamilies. The majority of GTPases function as binary switches that cycle between active GTP-bound and inactive GDP-bound states. This thesis will focus primarily on the biological functions of the Rho and Miro proteins. The Rho GTPases control the organization of the actin cytoskeleton and other associated activities, whereas the Miro GTPases are regulators of mitochondrial movement and morphology. A diverse array of cellular phenomena, including cell movement and intracellular membrane trafficking events, are dependent on cytoskeletal rearrangements mediated by Rho GTPases. Although human Rho GTPases are encoded by 20 distinct genes, most studies involving Rho GTPases have focused on the three representatives RhoA, Rac1 and Cdc42, which each regulate specific actin-dependent cellular processes. In an effort to compare the effects of all Rho GTPase members in the same cell system, we transfected constitutively active Rho GTPases in porcine aortic endothelial (PAE) cells and examined their effects on the organization of the actin cytoskeleton. We identified a number of previously undetected roles of the different members of the Rho GTPases. Moreover, we demonstrated that the downstream effectors of Rho GTPases have a broader specificity than previously thought. In a screen for novel Ras-like GTPases, we identified the Miro GTPases (Mitochondrial Rho). In our characterization of Miro, we established that these proteins influence mitochondrial morphology and serve functions in the transport of mitochondria along the microtubule system. Additionally, we provided evidence that Miro can be under control of calcium signaling pathways. Mitochondria are highly dynamic organelles that undergo continuous change in shape and distribution. Defects in mitochondrial dynamics are associated with several neurodegenerative diseases. In conclusion, our findings have contributed to a deeper understanding of the biological roles of Rho and Miro GTPases.
13.	Fransson, Åsa, et al. (author) The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking 2006 In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 344:2, s. 500-510 Journal article (peer-reviewed)abstract We recently described the atypical Rho GTPases Miro-1 and Miro-2. These proteins have tandem GTP-binding domains separated by a linker region with putative calcium-binding motives. In addition, the Miro GTPases have a C-terminal transmembrane domain, which confers targeting to the mitochondria. It was reported previously that a constitutively active mutant of Miro-1 induced a clustering of the mitochondria. This response can be separated into two distinct phenotypes: a formation of aggregated mitochondria and the appearance of thread-like mitochondria probably caused by defects in mitochondrial trafficking. The first GTPase domain is required for the clustering of the mitochondria, but the effect is not dependent on the EF-hands. Miro-2 only induces aggregation and not the formation of thread-like mitochondria. Moreover, we show that Miro interacts with the Kinesin-binding proteins, GRIF-1 and OIP106, suggesting that the Miro GTPases form a link between the mitochondria and the trafficking apparatus of the microtubules.
14.	Holmfeldt, Per, 1973- (author) Regulation of tubulin heterodimer partitioning during interphase and mitosis 2008 Doctoral thesis (other academic/artistic)abstract The microtubule cytoskeleton, which consists of dynamic polymers of alpha/beta tubulin heterodimers, organizes the cytoplasm and is essential for chromosome segregation during mitosis. My thesis addresses the significance and potential interplay between four distinct microtubule-regulatory proteins. The experimental approach included the development of a replicating vector system directing either constitutive expression of short hairpin RNAs or inducible ectopic expression, which allows stable depletion and/or conditional exchange of gene-products. Based on the originally observed activities in frog egg extracts, MCAK and TOGp have been viewed as major antagonistic proteins that regulate microtubule-dynamics throughout the cell cycle. Surprisingly, while my thesis work confirmed an essential role of these proteins to ensure mitotic fidelity, tubulin subunits partitioning is not controlled by the endogenous levels of MCAK and TOGp in human somatic cells. Our major discovery in these studies is that the activities of both CaMKII and TOGp are essential for spindle bipolarity through a mechanism involving protection of spindle microtubules against MCAK activity at the centrosome. In our search for the major antagonistic activities that regulates microtubule-dynamics in interphase cells, we found that the microtubule-destabilizing activity of Op18 is counteracted by MAP4. These studies also established Op18 and MAP4 as the predominant regulators of tubulin subunit partitioning in all three human cell model systems studied. Moreover, consistent with phosphorylation-inactivation of these two proteins during mitosis, we found that the microtubule-regulatory activities of both MAP4 and Op18 were only evident in interphase cells. Importantly, by employing a system for inducible gene product replacement, we found that site-specific phosphorylation-inactivation of Op18 is the direct cause of the demonstrated hyper-polymerization in response to T-cell antigen receptor triggering. This provides the first formally proven example of a signal transduction pathway for regulation of interphase microtubules. Op18 is frequently upregulated in various types of human malignancies. In addition, a somatic mutation of Op18 has recently been identified in an adenocarcinoma. This thesis work revealed that the mutant Op18 protein exerts increased microtubule-destabilizing activity. The mutant Op18 protein was also shown to be partially resistant to phosphorylation-inactivation during mitosis, which was associated with increased chromosome segregation aberrancies. Interestingly, we also observed the same phenotype by overexpressing the wild type Op18 protein. Thus, either excessive levels of wild type Op18 or normal levels of mutated hyper-active Op18 seems likely to contribute to tumor progression by exacerbating chromosomal instability.
15.	Johansson, Ann-Sofi, 1974- (author) RhoGTPase Signaling in Cell Polarity and Gene Regulation 2006 Doctoral thesis (other academic/artistic)abstract RhoGTPases are proteins working as molecular switches as they bind and hydrolyze GTP. They are in their active conformation when GTP is bound and are then able to interact with their effector proteins, which relay the downstream signaling. When the GTP is hydrolyzed to GDP, the RhoGTPase is inactivated. RhoGTPases have been shown to be activated by a variety of stimuli and they are implicated in regulation of diverse cellular processes, including cell migration, cell cycle progression, establishment of cell polarity and transformation. We identified mammalian Par6 as a novel effector protein for the RhoGTPases Cdc42 and Rac1. The Caenorhabditis elegans homologue of Par6 had previously been shown to be essential for cell polarity development in the worm embryo. We found that endogenous Par6 colocalized with the tight junction protein ZO-1 in MDCKII epithelial cells. Par6 also interacted with mammalian Par3, another member of the par (for partitioning defective) gene family, first identified in C.elegans. Endogenous Par3 also localized to tight junctions in epithelial cells. This suggested that Par6 and Par3 are part of a complex regulating cell polarity also in mammalian cells. The interaction between Par6 and activated Cdc42 and Rac1 suggested a role for these RhoGTPases in the regulation of this complex.Co-expression of Par6 together with PKCζ, induced a dramatic change in cell morphology. The cells rounded up and long cellular extensions, resembling neurites, were formed. The ability to induce these changes in cell morphology was found to be dependent on the direct interaction between Par6 and PKCζ, as well as on the kinase activity of PKCζ. We observed that cells co-expressing mPar6C and PKCζ contained bundled microtubules and microtubules that hade been acetylated, indicating that the microtubules were stabilized. To investigate the roles of RhoGTPases in PDGF-induced gene expression we performed cDNA microarray analyses on AG01518 human foreskin fibroblasts in which we over-expressed the dominant negative forms of Cdc42, Rac1 and RhoA. We found that the expression of 16 genes, out of the 45 up-regulated by PDGF-BB, were inhibited ≥50% in the presence of dominant negative Cdc42, Rac1 or RhoA. 19 other genes were down-regulated by one or two of the dominant RhoGTPases. Our data implied that the expression of many PDGF-BB induced genes can be affected by RhoGTPase signaling. In conclusion, the work presented here has increased the knowledge of the involvement of RhoGTPase signaling in establishment of cell polarity and gene regulation.
16.	MacAskill, Andrew F., et al. (author) Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. 2009 In: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 61:4, s. 541-555 Journal article (peer-reviewed)abstract Energy use, mainly to reverse ion movements in neurons, is a fundamental constraint on brain information processing. Trafficking of mitochondria to locations in neurons where there are large ion fluxes is essential for powering neural function. Mitochondrial trafficking is regulated by Ca2+ entry through ionotropic glutamate receptors, but the underlying mechanism is unknown. We show that the protein Miro1 links mitochondria to KIF5 motor proteins, allowing mitochondria to move along microtubules. This linkage is inhibited by micromolar levels of Ca2+ binding to Miro1. With the EF hand domains of Miro1 mutated to prevent Ca2+ binding, Miro1 could still facilitate mitochondrial motility, but mitochondrial stopping induced by glutamate or neuronal activity was blocked. Activating neuronal NMDA receptors with exogenous or synaptically released glutamate led to Miro1 positioning mitochondria at the postsynaptic side of synapses. Thus, Miro1 is a key determinant of how energy supply is matched to energy usage in neurons.
17.	Reis, Katarina, et al. (author) The Miro GTPases : at the heart of the mitochondrial transport machinery 2009 In: FEBS Letters. - : Elsevier B.V. on behalf of the Federation of European Biochemical Societies. - 0014-5793 .- 1873-3468. ; 583:9, s. 1391-1398 Research review (peer-reviewed)abstract Mitochondria are organelles of elaborate structure that in addition to supplying cellular energy, have significant roles in calcium homeostasis and apoptosis. Failure to maintain mitochondrial dynamics results in neurodegenerative diseases and neuromuscular pathologies. The Miro GTPases, which constitute a unique subgroup of the Ras superfamily, have emerged as essential regulators of mitochondrial morphogenesis and trafficking along microtubules. Miro GTPases function as calcium-dependent sensors in the control of mitochondrial motility. Increased awareness of the biological function of Miro GTPases can contribute to elucidate the molecular mechanisms underlying diseases caused by deregulated mitochondrial dynamics.
18.	Ruusala, Aino, et al. (author) Nck adapters are involved in the formation of dorsal ruffles, cell migration, and Rho signaling downstream of the platelet-derived growth factor beta receptor 2008 In: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 283:44, s. 30034-30044 Journal article (peer-reviewed)abstract The SH3 and SH2 domain-containing adapter proteins Nck1 and Nck2 are known to function downstream of activated tyrosine kinase receptors, such as the platelet-derived growth factor (PDGF) receptors. The SH2 domain of Nck1 binds to phosphorylated tyrosine residue 751 in PDGFbeta receptor and has been suggested to have a role in the PDGF-induced mobilization of the actin filament system. Because Tyr-751 is a site for additional receptor interactors, it has been difficult to discriminate the signaling from Nck from signaling via other molecules. For this reason we have used mouse embryonic fibroblasts derived from mice in which the genes for Nck1 and Nck2 have been inactivated by gene targeting (knock-out (KO) cells). The mutant cells had a reduced ability to form edge ruffles in response to PDGF, and the presence of Nck was obligatory for the formation of dorsal ruffles. In addition, the KO cells had a reduced chemotactic and migratory potential. Importantly, KO cells had reduced cell attachment properties and a reduced ability to form focal adhesions in response to serum stimulation. Moreover, signaling involving the Rho GTPases was defective in KO cells. In summary, our observations suggest that the Nck adapters are needed for signaling to Rho GTPases and actin dynamics downstream of the PDGFbeta receptor.
19.	Ruusala, Aino, et al. (author) The atypical Rho GTPase Wrch1 collaborates with the nonreceptor tyrosine kinases Pyk2 and Src in regulating cytoskeletal dynamics 2008 In: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 28:5, s. 1802-14 Journal article (peer-reviewed)abstract The Cdc42-like GTPase Wnt responsive Cdc42 homolog 1 (Wrch1) has several atypical features; it has an N-terminal proline-rich extension that confers binding to SH3 domains, and it harbors an extremely high intrinsic nucleotide exchange activity, which overrides the normal GTPase activity. As a result, Wrch1 resides mainly in the active, GTP-loaded conformation under normal cellular conditions. We have previously shown that ectopic expression of Wrch1 in fibroblasts resulted in an altered cell morphology visible as a formation of filopodia, a loss of stress fibers, and a reduction in focal adhesions. Here, we show that Wrch1 binds to the nonreceptor tyrosine kinase Pyk2. The interaction required Wrch1 to be in a GTP conformation and also required an intact N-terminal proline-rich extension as well as an intact effector loop. Wrch1 requires Pyk2 in imposing the cytoskeletal effects, seen as the formation of filopodia, since treatment of cells with a Pyk2-specific small interfering RNA abrogated this response. Interestingly, we found that the presence and activity of Src were needed for the formation of a Wrch1-Pyk2 complex as well as for the Wrch1-induced formation of filopodia. We propose a model in which Pyk2 and Src function to coordinate the Wrch1-dependent effects on cytoskeletal dynamics.
20.	Saotome, Masao, et al. (author) Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase 2008 In: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Sciences of the USA. - 0027-8424 .- 1091-6490. ; 105:52, s. 20728-20733 Journal article (peer-reviewed)abstract Calcium oscillations suppress mitochondrial movements along the microtubules to support on-demand distribution of mitochondria. To activate this mechanism, Ca(2+) targets a yet unidentified cytoplasmic factor that does not seem to be a microtubular motor or a kinase/phosphatase. Here, we have studied the dependence of mitochondrial dynamics on the Miro GTPases that reside in the mitochondria and contain two EF-hand Ca(2+)-binding domains, in H9c2 cells and primary neurons. At resting cytoplasmic [Ca(2+)] ([Ca(2+)](c)), movements of the mitochondria were enhanced by Miro overexpression irrespective of the presence of the EF-hands. The Ca(2+)-induced arrest of mitochondrial motility was also promoted by Miro overexpression and was suppressed when either the Miro were depleted or their EF-hand was mutated. Miro also enhanced the fusion state of the mitochondria at resting [Ca(2+)](c) but promoted mitochondrial fragmentation at high [Ca(2+)](c). These effects of Miro on mitochondrial morphology seem to involve Drp1 suppression and activation, respectively. In primary neurons, Miro also caused an increase in dendritic mitochondrial mass and enhanced mitochondrial calcium signaling. Thus, Miro proteins serve as a [Ca(2+)](c)-sensitive switch and bifunctional regulator for both the motility and fusion-fission dynamics of the mitochondria.
21.	Viklund, Ing-Marie, et al. (author) WAFL, a new protein involved in regulation of early endocytictransport at the intersection of actin and microtubule dynamics 2009 In: Experimental Cell Research. - : Elsevier Inc.. - 0014-4827 .- 1090-2422. ; 315:6, s. 1040-1052 Journal article (peer-reviewed)abstract We have previously identified a new gene with sequence homology to the WASP-family of actin regulators denoted WAFL (WASP and FKBP-like). Here we report a possible biological function for WAFL, by demonstrating an association to early endosomes via its central coiled-coil domain. Further we show by functional and structural studies that WAFL is associated with both microtubules and the actin filament system, the two means of transport of early endosomes. In addition, WAFL interacts with WASP-interacting protein (WIP) and actin, thus linking WAFL to actin dynamics. The use of RNAi depletion of WAFL shows that WAFL-deficient cells display delayed transport of endosomal cargo. Our findings are compatible with a model wherebyWAFL is involved in the transport of early endosomes at the level of transition between microfilamentbased and microtubule-based movement.

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