RON receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant.
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RON receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant. / Eckerich, Carmen; Schulte, Alexander; Martens, Tobias; Zapf, Svenja; Westphal, Manfred; Lamszus, Katrin.
In: J NEUROCHEM, Vol. 109, No. 4, 4, 05.2009, p. 969-980.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - RON receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant.
AU - Eckerich, Carmen
AU - Schulte, Alexander
AU - Martens, Tobias
AU - Zapf, Svenja
AU - Westphal, Manfred
AU - Lamszus, Katrin
PY - 2009/5
Y1 - 2009/5
N2 - Malignant gliomas are incurable because of their diffuse infiltration of the surrounding brain. The recepteur d'origine nantais (RON) receptor tyrosine kinase is highly expressed in several epithelial cancer types and mediates tumorigenic, pro-invasive as well as metastatic effects. Analyzing RON expression in human gliomas, we found that different splice variants with known oncogenic activity are expressed in glioblastomas (GBM). In addition, the RON ligand macrophage-stimulating protein (MSP) is secreted by cultured GBM cells. MSP showed no mitogenic effect on GBM cells but displayed significant chemotactic activity for several GBM cell lines. We identified a novel splice variant, RONDelta90, which is generated by a transcript missing exon 6. As a result of a frameshift, translation is terminated in exon 7, resulting in a truncated soluble protein. RONDelta90 transcripts are expressed in normal human brain as well as in low grade astrocytomas but only in approximately 50% of highly malignant astrocytomas. In addition, RONDelta90 is detectable in supernatants of GBM cell lines. We cloned the RONDelta90 cDNA, and purified the recombinant protein from transfected cells. RONDelta90 inhibited MSP-induced phosphorylation of cellular RON and also attenuated basal activation levels. In addition, RONDelta90 inhibited MSP-induced glioma cell migration as well as random motility. To conclude, RONDelta90 is a novel soluble receptor variant with antagonistic activity that may act as a physiological modulator of RON signaling. The expression of several oncogenic RON splice variants in malignant gliomas suggests that these could represent candidate targets for treatment with agents inhibiting RON activity.
AB - Malignant gliomas are incurable because of their diffuse infiltration of the surrounding brain. The recepteur d'origine nantais (RON) receptor tyrosine kinase is highly expressed in several epithelial cancer types and mediates tumorigenic, pro-invasive as well as metastatic effects. Analyzing RON expression in human gliomas, we found that different splice variants with known oncogenic activity are expressed in glioblastomas (GBM). In addition, the RON ligand macrophage-stimulating protein (MSP) is secreted by cultured GBM cells. MSP showed no mitogenic effect on GBM cells but displayed significant chemotactic activity for several GBM cell lines. We identified a novel splice variant, RONDelta90, which is generated by a transcript missing exon 6. As a result of a frameshift, translation is terminated in exon 7, resulting in a truncated soluble protein. RONDelta90 transcripts are expressed in normal human brain as well as in low grade astrocytomas but only in approximately 50% of highly malignant astrocytomas. In addition, RONDelta90 is detectable in supernatants of GBM cell lines. We cloned the RONDelta90 cDNA, and purified the recombinant protein from transfected cells. RONDelta90 inhibited MSP-induced phosphorylation of cellular RON and also attenuated basal activation levels. In addition, RONDelta90 inhibited MSP-induced glioma cell migration as well as random motility. To conclude, RONDelta90 is a novel soluble receptor variant with antagonistic activity that may act as a physiological modulator of RON signaling. The expression of several oncogenic RON splice variants in malignant gliomas suggests that these could represent candidate targets for treatment with agents inhibiting RON activity.
KW - Blotting, Western
KW - Brain Neoplasms
KW - Cell Line, Tumor
KW - Cell Movement
KW - Cell Proliferation
KW - DNA, Complementary
KW - Exons
KW - Glioma
KW - Humans
KW - Immunohistochemistry
KW - Ligands
KW - Microscopy, Fluorescence
KW - Receptor Protein-Tyrosine Kinases
KW - Reverse Transcriptase Polymerase Chain Reaction
U2 - 10.1111/j.1471-4159.2009.06027.x
DO - 10.1111/j.1471-4159.2009.06027.x
M3 - SCORING: Journal article
C2 - 19519771
VL - 109
SP - 969
EP - 980
JO - J NEUROCHEM
JF - J NEUROCHEM
SN - 0022-3042
IS - 4
M1 - 4
ER -
