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Gewählte Publikation:

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Publikationstyp: Zeitschriftenaufsatz
Dokumentart: Originalarbeit

Publikationsjahr: 2017

AutorInnen: Edlinger, L; Berger-Becvar, A; Menzl, I; Hoermann, G; Greiner, G; Grundschober, E; Bago-Horvath, Z; Al-Zoughbi, W; Hoefler, G; Brostjan, C; Gille, L; Moriggl, R; Spittler, A; Sexl, V; Hoelbl-Kovacic, A

Titel: Expansion of BCR/ABL1(+) cells requires PAK2 but not PAK1.

Quelle: Br J Haematol. 2017; 179(2):229-241



Autor/innen der Vetmeduni Vienna:

Bago-Horvath Zsuzsanna Agnes,
Berger-Becvar Angelika,
Edlinger Leo,
Gille Lars,
Grundschober Eva,
Hölbl-Kovacic Andrea,
Menzl Ingeborg,
Moriggl Richard,
Sexl Veronika,

Beteiligte Vetmed-Organisationseinheiten
Abteilung für Funktionelle Krebsgenomik,
Institut für Pharmakologie und Toxikologie,


Zugehörige(s) Projekt(e): Stat5 Serin-Phosphorylierung in Bcr/Abl-induzierter Leukämie

Jak Stat - Signalling from Basis to Disease


Abstract:
The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1(+) haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2- but not shPAK1-expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2-deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome-mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.

Keywords Pubmed: Animals
Cell Line, Tumor
Cell Proliferation*
Endothelial Cells/metabolism
Endothelial Cells/pathology
Exosomes/genetics
Exosomes/metabolism
Exosomes/pathology
Extracellular Matrix/genetics
Extracellular Matrix/metabolism
Extracellular Matrix/pathology
Fusion Proteins, bcr-abl/genetics
Fusion Proteins, bcr-abl/metabolism*
Hematologic Neoplasms/genetics
Hematologic Neoplasms/metabolism*
Hematologic Neoplasms/pathology
Humans
Leukemia/genetics
Leukemia/metabolism*
Leukemia/pathology
Lymphoma/genetics
Lymphoma/metabolism*
Lymphoma/pathology
Mice
Mice, Inbred NOD
Neovascularization, Pathologic/genetics
Neovascularization, Pathologic/metabolism
Neovascularization, Pathologic/pathology
p21-Activated Kinases/genetics
p21-Activated Kinases/metabolism*


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