Mathias Bergman
University of Helsinki
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Featured researches published by Mathias Bergman.
Molecular and Cellular Biology | 1995
Mathias Bergman; Vladimir Joukov; Ismo Virtanen; Kari Alitalo
The C-terminal Src kinase p50csk phosphorylates Src family tyrosine kinases and down-regulates their activity in vitro. To gain insight into the cellular functions of this potentially antioncogenic enzyme, we have overexpressed the csk cDNA by using an inducible promoter in HeLa cells. Despite some differences in basal Src activity in the clones analyzed, Src activity was not significantly suppressed, while the amount of p50csk and Csk activity increased at least 10-fold during 3 days of induction. Immunofluorescence for the induced p50csk was localized in the cytoplasm and distinctly in focal adhesions, in which the amount of phosphotyrosine containing proteins was also increased. Point and deletion mutagenesis experiments showed that localization in focal adhesions was dependent on the SH2 and SH3 domains of Csk but not on its catalytic activity. Csk formed a complex with the focal adhesion protein paxillin in cells, and its SH2 domain was shown to interact with pp125FAK and paxillin in vitro. After Csk induction, the cells became spherical and more loosely attached to the culture substratum, and the alpha v beta 5 integrin complex (vitronectin receptor) of focal adhesions was redistributed to a novel type of structure consisting of punctate plaques on the ventral cell surface. These phenotypic changes occurred in several clones analyzed and were totally reversible when Csk was switched off, but they did not occur in cells overexpressing the catalytically inactive Csk R-222 mutant or luciferase. Our results thus show that a fraction of cellular Csk is targeted to focal adhesions via its SH2 and SH3 domains, probably interacting with tyrosyl-phosphorylated focal adhesion proteins. They also suggest that Csk is involved in the regulation of integrins controlling cell attachment and shape.
Molecular and Cellular Biology | 1994
Matti Autero; J Saharinen; Tiina Pessa-Morikawa; M Soula-Rothhut; C Oetken; M Gassmann; Mathias Bergman; Kari Alitalo; P Burn; Carl G. Gahmberg
Src family protein tyrosine kinases (PTKs) play an essential role in antigen receptor-initiated lymphocyte activation. Their activity is largely regulated by a negative regulatory tyrosine which is a substrate for the activating action of the CD45 phosphotyrosine phosphatase (PTPase) or, conversely, the suppressing action of the cytosolic p50csk PTK. Here we report that CD45 was phosphorylated by p50csk on two tyrosine residues, one of them identified as Tyr-1193. This residue was not phosphorylated by T-cell PTKs p56lck and p59fyn. Tyr-1193 was phosphorylated in intact T cells, and phosphorylation increased upon treatment with PTPase inhibitors, indicating that this tyrosine is a target for a constitutively active PTK. Cotransfection of CD45 and csk into COS-1 cells caused tyrosine phosphorylation of CD45 in the intact cells. Tyrosine-phosphorylated CD45 bound p56lck through the SH2 domain of the kinase. Finally, p50csk-mediated phosphorylation of CD45 caused a severalfold increase in its PTPase activity. Our results show that direct tyrosine phosphorylation of CD45 can affect its activity and association with Src family PTKs and that this phosphorylation could be mediated by p50csk. If this is also true in the intact cells, it adds a new dimension to the physiological function of p50csk in T lymphocytes.
Journal of Clinical Oncology | 2002
Merja Auvinen; Eero Sihvo; Terhi Ruohtula; Jukka T. Salminen; Aki Koivistoinen; Päivi Siivola; Ragna Rönnholm; Juhani O. Ramo; Mathias Bergman; Jarmo A. Salo
PURPOSE Barretts esophagus (BE), a precancerous condition for Barretts adenocarcinoma, is classically characterized by flames of salmon-colored mucosa extending into normal pale esophageal mucosa. This flaming is thought to be a consequence of continuous erosis of mucosa caused by chronic reflux. Another characteristic feature of Barretts adenocarcinoma patients is the frequent development of lymph node metastases. We addressed whether onset of angiogenesis occurs in BE and if the lymphatic system might provide a route for Barretts adenocarcinoma cells to infiltrate regular lymph nodes. PATIENTS AND METHODS Fifteen surgically resected Barretts dysplasia or adenocarcinoma patients were included. Immunohistochemistry and a modified whole mount analysis were used. RESULTS The incipient angiogenesis originates from the pre-existing vascular network in the lamina propria and infiltrates Barretts epithelium, giving its ominous salmon-red color. Barretts epithelium-specific goblet cells express vascular endothelial growth factor (VEGF)-A. The immature blood vessels show a relative absence of smooth muscle actin (SMA)-positive mural cells and express VEGF receptor (VEGFR)-2 and matrix metalloproteinase (MMP)-9 on their exterior. Coexpression of VEGF-C and its receptor VEGFR-3 on lymphatic vessels is demonstrated. CONCLUSION BE is strongly neovascularized not eroded. This novel concept of a molecular mechanism of the origin of BE might emphasize why precancerous BE can give rise to the more cancerous dysplasia and Barretts adenocarcinoma stages. In addition, adenocarcinoma cells induce lymphangiogenesis. The new lymphangiogenic vessels might provide a systemic route for adenocarcinoma cells to invade circulation and induce lymph node metastasis.
Biochemical Journal | 2000
Kirsi Paukku; Sigrídur Valgeirsdóttir; Pipsa Saharinen; Mathias Bergman; Carl-Henrik Heldin; Olli Silvennoinen
Several growth factors activate signal transducers and activators of transcription (Stats) but the mechanism of Stat activation in receptor tyrosine kinase signalling has remained elusive. In the present study we have analysed the roles of different platelet-derived growth factor (PDGF)-induced tyrosine kinases in the activation of Stat5. Co-expression experiments in insect and mammalian cells demonstrated that both PDGF beta-receptor (PDGF beta-R) and Jak1, but not c-Src, induced the activation of Stat5. Furthermore, immune-complex-purified PDGF beta-R was able to phosphorylate Stat5 directly. The role of the cytoplasmic tyrosine kinases in the PDGF-induced activation of Stat5 was further investigated by overexpressing kinase-negative (KN) and wild-type Jak and c-Src kinases. Jak1-KN or Jak2-KN had no effect but both Src-KN and wild-type c-Src similarly decreased the PDGF-beta-R-induced activation of Stat5. The activation of both Src and Stat5 is dependent on the same tyrosine residues Tyr(579) and Tyr(581) in PDGF beta-R; thus the observed inhibition by Src might result from competition for binding of Stat5 to the receptor. Finally, fibroblasts derived from Src(-/-) and Fyn(-/-) mice showed normal pattern of PDGF-induced tyrosine phosphorylation of Stat5. Taken together, these results indicate that Stat5 is a direct substrate for PDGF beta-R and that the activation does not require Jak1, Jak2, c-Src or Fyn tyrosine kinases.
Cytogenetic and Genome Research | 1992
Elina Armstrong; L. Cannizzaro; Mathias Bergman; Kay Huebner; Kari Alitalo
We have previously reported the cloning of a novel cytoplasmic tyrosine kinase, CSK. This tyrosine kinase has been shown to downregulate the tyrosine kinase activity of the c-src oncoprotein through tyrosine phosphorylation of the c-src carboxyl terminus. Cell transformation by src oncoproteins is caused by several oncogenic mechanisms, which interfere with this phosphorylation. The CSK gene could therefore potentially function as an antioncogene. We have here mapped the CSK gene to 15q23----q25 by in situ hybridization.
FEBS Letters | 2003
Esa T. Mikkola; Mathias Bergman
The crystal structure of full‐length Csk (C‐terminal Src kinase) molecules shows a hydrophobic interaction between the SH2–kinase linker residue Phe183 and the αC‐helix of the catalytic domain. To study the possible involvement of this contact in the regulation of the activity of Csk and CHK (Csk homologous kinase), a Csk SH2–kinase linker deletion mutant, Csk Phe183 and CHK Leu223 point mutants were analyzed. It was observed that a residue with a long hydrophobic side chain in position 183 (Csk) and 223 (CHK) is required to sustain the catalytic activity of Csk and CHK. These results suggest that Csk Phe183 and CHK Leu223 stabilize the movement of the αC‐helix of these protein tyrosine kinases.
Journal of Biological Chemistry | 1994
Satu Vainikka; Vladimir Joukov; Stefan Wennström; Mathias Bergman; Pier Giuseppe Pelicci; Kari Alitalo
Cell Growth & Differentiation | 1994
William G. Cance; RoIf J. Craven; Mathias Bergman; LiHui Xu; Kari Alitalo; Edison T. Liu
Oncogene | 1991
Johanna I. Partanen; Elina Armstrong; Mathias Bergman; Tomi P. Mäkelä; Harri Hirvonen; Kay Huebner; Kari Alitalo
The International Journal of Biochemistry & Cell Biology | 2003
Merja Auvinen; Kristiina Järvinen; Anneli Hotti; Juha Okkeri; Jens Laitinen; Olli A. Jänne; Philip Coffino; Mathias Bergman; Leif C. Andersson; Kari Alitalo; Erkki Hölttä