Cancer research (Chicago, Ill.), 2012-08, Vol.72 (15), p.3764-3774
2012
Details
- Autor(en) / Beteiligte
- Titel
- The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation
- Ist Teil von
- Cancer research (Chicago, Ill.), 2012-08, Vol.72 (15), p.3764-3774
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Patients with lung cancer often present with metastatic disease and therefore have a very poor prognosis. The recent discovery of several novel ROS receptor tyrosine kinase molecular alterations in non-small cell lung cancer (NSCLC) presents a therapeutic opportunity for the development of new targeted treatment strategies. Here, we report that the NSCLC-derived fusion CD74-ROS, which accounts for 30% of all ROS fusion kinases in NSCLC, is an active and oncogenic tyrosine kinase. We found that CD74-ROS-expressing cells were highly invasive in vitro and metastatic in vivo. Pharmacologic inhibition of CD74-ROS kinase activity reversed its transforming capacity by attenuating downstream signaling networks. Using quantitative phosphoproteomics, we uncovered a mechanism by which CD74-ROS activates a novel pathway driving cell invasion. Expression of CD74-ROS resulted in the phosphorylation of the extended synaptotagmin-like protein E-Syt1. Elimination of E-Syt1 expression drastically reduced invasiveness both in vitro and in vivo without modifying the oncogenic activity of CD74-ROS. Furthermore, expression of CD74-ROS in noninvasive NSCLC cell lines readily conferred invasive properties that paralleled the acquisition of E-Syt1 phosphorylation. Taken together, our findings indicate that E-Syt1 is a mediator of cancer cell invasion and molecularly define ROS fusion kinases as therapeutic targets in the treatment of NSCLC.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-11-3990Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3753671
- Format
- –
- Schlagworte
- Animals, Antigens, Differentiation, B-Lymphocyte - genetics, Antigens, Differentiation, B-Lymphocyte - metabolism, Antigens, Differentiation, B-Lymphocyte - physiology, Antineoplastic agents, Biological and medical sciences, Carcinoma, Non-Small-Cell Lung - genetics, Carcinoma, Non-Small-Cell Lung - metabolism, Carcinoma, Non-Small-Cell Lung - pathology, Cells, Cultured, Gene Expression Regulation, Neoplastic, Histocompatibility Antigens Class II - genetics, Histocompatibility Antigens Class II - metabolism, Histocompatibility Antigens Class II - physiology, Humans, Intracellular Calcium-Sensing Proteins - metabolism, Lung Neoplasms - genetics, Lung Neoplasms - metabolism, Lung Neoplasms - pathology, Medical sciences, Membrane Proteins - metabolism, Mice, Mice, SCID, Neoplasm Invasiveness - genetics, Oncogene Proteins, Fusion - genetics, Oncogene Proteins, Fusion - metabolism, Oncogene Proteins, Fusion - physiology, Pharmacology. Drug treatments, Phosphorylation - genetics, Pneumology, Protein-Tyrosine Kinases - genetics, Protein-Tyrosine Kinases - metabolism, Protein-Tyrosine Kinases - physiology, Proto-Oncogene Proteins - genetics, Proto-Oncogene Proteins - metabolism, Proto-Oncogene Proteins - physiology, Rats, Signal Transduction - genetics, Tumors, Tumors of the respiratory system and mediastinum