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Aspenström, Pontus
Publications (10 of 26) Show all publications
Aspenström, P. (2019). The Intrinsic GDP/GTP Exchange Activities of Cdc42 and Rac1 Are A Critical Determinants for Their Specific Effects on Mobilization of the Actin Filament System. CELLS, 8(7), Article ID 759.
Open this publication in new window or tab >>The Intrinsic GDP/GTP Exchange Activities of Cdc42 and Rac1 Are A Critical Determinants for Their Specific Effects on Mobilization of the Actin Filament System
2019 (English)In: CELLS, ISSN 2073-4409, Vol. 8, no 7, article id 759Article in journal (Refereed) Published
Abstract [en]

The Rho GTPases comprise a subfamily of the Ras superfamily of small GTPases. Their importance in regulation of cell morphology and cell migration is well characterized. According to the prevailing paradigm, Cdc42 regulates the formation of filopodia, Rac1 regulates the formation of lamellipodia, and RhoA triggers the assembly of focal adhesions. However, this scheme is clearly an oversimplification, as the Rho subfamily encompasses 20 members with diverse effects on a number of vital cellular processes, including cytoskeletal dynamics and cell proliferation, migration, and invasion. This article highlights the importance of the catalytic activities of the classical Rho GTPases Cdc42 and Rac1, in terms of their specific effects on the dynamic reorganization of the actin filament system. GTPase-deficient mutants of Cdc42 and Rac1 trigger the formation of broad lamellipodia and stress fibers, and fast-cycling mutations trigger filopodia formation and stress fiber dissolution. The filopodia response requires the involvement of the formin family of actin nucleation promotors. In contrast, the formation of broad lamellipodia induced by GTPase-deficient Cdc42 and Rac1 is mediated through Arp2/3-dependent actin nucleation.

Keywords
fast-cycling, Rho GTPases, Cdc42, Rac, filopodia, actin
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-393133 (URN)10.3390/cells8070759 (DOI)000478902000023 ()31330900 (PubMedID)
Funder
Swedish Cancer Society, CAN 2018/0419
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Aspenström, P. (2018). Activated Rho GTPases in Cancer-The Beginning of a New Paradigm. International Journal of Molecular Sciences, 19(12), Article ID 3949.
Open this publication in new window or tab >>Activated Rho GTPases in Cancer-The Beginning of a New Paradigm
2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 12, article id 3949Article, review/survey (Refereed) Published
Abstract [en]

Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted to regulation of cytoskeletal dynamics, cell morphogenesis, and cell locomotion, with initially no clear indications of direct involvement in cancer progression. This paradigm has been challenged by numerous observations that Rho-regulated pathways are often dysregulated in cancers. More recently, identification of point mutants in the Rho GTPases Rac1, RhoA, and Cdc42 in human tumors has finally given rise to a new paradigm, and we can now state with confidence that Rho GTPases serve as oncogenes in several human cancers. This article provides an expose of current knowledge of the roles of activated Rho GTPases in cancers.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
Rho GTPases, atypical Rho GTPases, oncogenes, actin, stress fibers, cell migration
National Category
Cancer and Oncology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-376315 (URN)10.3390/ijms19123949 (DOI)000455323500251 ()30544828 (PubMedID)
Funder
Swedish Cancer Society, 2017/527
Available from: 2019-02-04 Created: 2019-02-04 Last updated: 2019-02-04Bibliographically approved
Ruusala, A. & Aspenström, P. (2008). The atypical Rho GTPase Wrch1 collaborates with the nonreceptor tyrosine kinases Pyk2 and Src in regulating cytoskeletal dynamics. Molecular and Cellular Biology, 28(5), 1802-14
Open this publication in new window or tab >>The atypical Rho GTPase Wrch1 collaborates with the nonreceptor tyrosine kinases Pyk2 and Src in regulating cytoskeletal dynamics
2008 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 28, no 5, p. 1802-14Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Wrch1, Rho GTPase, Pyk2, FAK, focal adhesion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-12868 (URN)10.1128/MCB.00201-07 (DOI)000253603100032 ()18086875 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-11Bibliographically approved
Aase, K., Ernkvist, M., Ebarasi, L., Jakobsson, L., Majumdar, A., Yi, C., . . . Holmgren, L. (2007). Angiomotin regulates endothelial cell migration during embryonic angiogenesis. Genes & Development, 21(16), 2055-2068
Open this publication in new window or tab >>Angiomotin regulates endothelial cell migration during embryonic angiogenesis
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2007 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 16, p. 2055-2068Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Angiostatin, neovascularization, embryogenesis, GTPase, chemotaxis, transgenic, zebrafish
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-11544 (URN)10.1101/gad.432007 (DOI)000248789800010 ()17699752 (PubMedID)
Available from: 2007-09-26 Created: 2007-09-26 Last updated: 2017-12-11Bibliographically approved
Aspenström, P., Ruusala, A. & Pacholsky, D. (2007). Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases. Experimental Cell Research, 313(17), 3673-3679
Open this publication in new window or tab >>Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases
2007 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 313, no 17, p. 3673-3679Article, review/survey (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-11585 (URN)10.1016/j.yexcr.2007.07.022 (DOI)000250169700001 ()17850788 (PubMedID)
Available from: 2007-10-03 Created: 2007-10-03 Last updated: 2017-12-11Bibliographically approved
Aspenström, P., Fransson, Å. & Richnau, N. (2006). Pombe Cdc15 homology proteins: regulators of membrane dynamics and the actin cytoskeleton. TIBS -Trends in Biochemical Sciences. Regular ed., 31(12), 670-679
Open this publication in new window or tab >>Pombe Cdc15 homology proteins: regulators of membrane dynamics and the actin cytoskeleton
2006 (English)In: TIBS -Trends in Biochemical Sciences. Regular ed., ISSN 0968-0004, E-ISSN 1362-4326, Vol. 31, no 12, p. 670-679Article, review/survey (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-19719 (URN)10.1016/j.tibs.2006.10.001 (DOI)000242873100004 ()17074490 (PubMedID)
Available from: 2006-12-01 Created: 2006-12-01 Last updated: 2017-12-08Bibliographically approved
Aspenström, P., Richnau, N. & Johansson, A.-S. (2006). The diaphanous-related formin DAAM1 collaborates with the Rho GTPases RhoA and Cdc42, CIP4 and Src in regulating cell morphogenesis and actin dynamics. Experimental Cell Research, 312(12), 2180-2194
Open this publication in new window or tab >>The diaphanous-related formin DAAM1 collaborates with the Rho GTPases RhoA and Cdc42, CIP4 and Src in regulating cell morphogenesis and actin dynamics
2006 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 312, no 12, p. 2180-2194Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
CIP4, Diaphanous, Actin, Rho, Cdc42, Src
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-80951 (URN)10.1016/j.yexcr.2006.03.013 (DOI)16630611 (PubMedID)
Available from: 2006-07-05 Created: 2006-07-05 Last updated: 2017-12-14Bibliographically approved
Aspenström, P. (2006). The verprolins as regulators of actin dynamics.. In: Actin-monomer-binding proteins. (pp. 97-106). Austin, Texas: Landes Biosciences
Open this publication in new window or tab >>The verprolins as regulators of actin dynamics.
2006 (English)In: Actin-monomer-binding proteins., Austin, Texas: Landes Biosciences , 2006, p. 97-106Chapter in book (Refereed)
Abstract [en]

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.

Place, publisher, year, edition, pages
Austin, Texas: Landes Biosciences, 2006
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10324 (URN)10.1007/978-0-387-46407-7 (DOI)978-0-387-46405-3 (ISBN)
Available from: 2007-03-15 Created: 2007-03-15 Last updated: 2011-02-28Bibliographically approved
Edlund, S., Lee, S. Y., Grimsby, S., Zhang, S., Aspenström, P., Heldin, C.-H. & Landström, M. (2005). Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. Molecular and Cellular Biology, 25(4), 1475-1488
Open this publication in new window or tab >>Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis
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2005 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 25, no 4, p. 1475-1488Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Animals, Apoptosis/drug effects/*physiology, COS Cells, Cell Fractionation, Cercopithecus aethiops, Cytoskeletal Proteins/*metabolism, DNA-Binding Proteins/*metabolism, Glycogen Synthase Kinase 3/metabolism, Humans, Male, Mice, Phosphorylation/drug effects, Prostatic Neoplasms/metabolism, Protein Binding/drug effects, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins/metabolism, RNA; Small Interfering/metabolism, Research Support; Non-U.S. Gov't, Serine/metabolism, Trans-Activators/*metabolism, Transcription Factors/*metabolism, Transforming Growth Factor beta/*pharmacology, Tumor Cells; Cultured, p38 Mitogen-Activated Protein Kinases/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-72728 (URN)10.1128/MCB.25.4.1475-1488.2005 (DOI)15684397 (PubMedID)
Available from: 2005-05-27 Created: 2005-05-27 Last updated: 2017-12-14Bibliographically approved
Aspenström, P. (2005). The verprolin family of proteins: Regulators of cell morphogenesis and endocytosis. FEBS Letters, 579(24), 5253-5259
Open this publication in new window or tab >>The verprolin family of proteins: Regulators of cell morphogenesis and endocytosis
2005 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 579, no 24, p. 5253-5259Article, review/survey (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-74762 (URN)10.1016/j.febslet.2005.08.053 (DOI)16182290 (PubMedID)
Available from: 2005-11-14 Created: 2005-11-14 Last updated: 2017-12-14Bibliographically approved
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