ROS Fusion Tyrosine Kinase Activates a SH2 Domain–Containing Phosphatase-2/Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Signaling Axis to Form Glioblastoma in Mice

Abstract

Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domaincontaining phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches. (Cancer Res 2006; 66(15): 7473-81)

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

“…The molecular mechanism through which ROS regulates tyrosine phosphorylation of SHP2 remains unclear. The Src family protein tyrosine kinase Fyn may act upstream of SHP2 phosphorylation at the C-terminal tyrosine residues (61), and ROS fusion tyrosine kinase may activate SHP2, causing subsequent tyrosine phosphorylation of SHP2 (62). These studies support the possibility that ROS may indirectly facilitate SHP2 phosphorylation (8).…”

Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

“…To test the idea that inactivation of ROS1 could modulate vascular remodeling in vivo, we administered genistein previously shown regulate ROS1 function (23,24). When s-glutathiolation was induced in HEK293T cells transfected with myctagged SHP-1 or SHP-2 plasmid, we noted s-glutathiolation of SHP-2 ( Figure 8C) following IP.…”

A Conserved Rod Domain Phosphotyrosine That Is Targeted by the Phosphatase PTP1B Promotes Keratin 8 Protein Insolubility and Filament Organization*

“…The detection of K8 phospho-tyrosine peptides in lung cancer was associated with those tissues and cell lines that had high expression of the proto-oncogene tyrosine kinase ROS (31). ROS is an orphan receptor tyrosine kinase that controls cell survival, growth, differentiation, and proliferation pathways via its ability to form oncogenic fusion proteins (39). ROS fusions are common in cholangiocarcinoma (28), a highly aggressive form of hepatocellular carcinoma with poorly understood molecular mechanisms.…”