Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
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.
Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1.
Br J Haematol. 2017; 179(2):229-241
Doi: 10.1111/bjh.14833
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- Leading authors Med Uni Graz
- Edlinger Leo
- Co-authors Med Uni Graz
- Al-Zoughbi Wael
- Höfler Gerald
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Cell Line, Tumor - administration & dosage
- Cell Proliferation - administration & dosage
- Endothelial Cells - metabolism, pathology
- Exosomes - genetics, metabolism, pathology
- Extracellular Matrix - genetics, metabolism, pathology
- Fusion Proteins, bcr-abl - genetics, metabolism
- Hematologic Neoplasms - genetics, metabolism, pathology
- Humans - administration & dosage
- Leukemia - genetics, metabolism, pathology
- Lymphoma - genetics, metabolism, pathology
- Mice - administration & dosage
- Mice, Inbred NOD - administration & dosage
- Neovascularization, Pathologic - genetics, metabolism, pathology
- p21-Activated Kinases - genetics, metabolism
- Find related publications in this database (Keywords)
- PAK2
- BCR/ABL1
- CML
- lymphoma
- p21-activated kinases
- exosomes