DNA tumor viruses such as simian virus 40 (SV40) express dominant acting oncoproteins that exert their effects by associating with key cellular targets and altering the signaling pathways they govern. Thus, tumor viruses have proved to be invaluable aids in identifying proteins that participate in tumorigenesis, and in understanding the molecular basis for the transformed phenotype. The roles played by the SV40-encoded 708 aminoacid large T antigen (T antigen), and 174 amino acid small T antigen (t antigen), in transformation have been examined extensively. These studies have firmly established that large T antigen's inhibition of the p53 and Rbfamily of tumor suppressors and small T antigen's action on the pp2A phosphatase, are important for SV40-induced transformation. It is not yet clear if the Rb, p53 and pp2A proteins are the only targets through which SV40 transforms cells, or whether additional targets await discovery. Finally, expression of SV40 oncoproteins in transgenic mice results in effects ranging from hyperplasia to invasive carcinoma accompanied by metastasis, depending on the tissue in which they are expressed. Thus, the consequences of SV40 action on these targets depend on the cell type being studied. The identification of additional cellular targets important for transformation, and understanding the molecular basis for the cell type-specific action of the viral T antigens are two important areas through which SV40 will continue to contribute to our understanding of cancer.
About 25% of breast cancers harbor the amplified oncogene HER2 and are dependent on HER2 kinase function, identifying HER2 as a vulnerable target for therapy. However,. HER2-HER3 activation is buffered so that it is protected against a nearly two log inhibition of HER2 catalytic activity; this buffering is driven by the negative regulation of HER3 by Akt. We have now further characterized HER2-HER3 signaling activity and shown that the compensatory buffering prevents apoptotic tumor cell death from occurring as a result of the combined loss of MAPK and Akt signaling. To overcome the cancer cells' compensatory mechanisms, we co-administered a PI3K/ mTor inhibitor and a HER2 tyrosinc kinase inhibitor. This treatment strategy proved suboptimal because it induced both tyrosine kinase inhibitor sensitizing and desensitizing effects and robust cross-compensation of MAPK and Akt signaling pathways. Noting that HER2-HER3 activity was completely inhibited by higher, fully inactivating doses of TKI, we then attempted to overcome the cells compensatory buffering with this higher dose. This treatment crippled all downstream signaling and induced tumor apoptosis. Although such high doses of TKI are toxic in vivo when given continuously, we found that intermittent doses of TKI administered to mice produced sequential cycles of tumor apoptosis and ultimately complete tumor regression in mouse models, with much less toxicity. This strategy for inactivation of HER2-HER3 tumorigenic activity is proposed for clinical testing.
Trask is a recently described transmembrane substrate of Src kinases whose expression and phosphorylation has been correlated with the biology of some cancers. Little is known about the molecular functions of Trask, although its phosphorylation has been associated with cell adhesion. We have studied the effects of Trask phosphorylation on cell adhesion, integrin activation, clustering, and focal adhesion signaling. The small hairpin RNA (shRNA) knockdown of Trask results in increased cell adhesiveness and a failure to properly inactivate focal adhesion signaling, even in the unanchored state. On the contrary, the experimentally induced phosphorylation of Trask results in the inhibition of cell adhesion and inhibition of focal adhesion signaling. This is mediated through the inhibition of integrin clustering without affecting integrin affinity state or ligand binding activity. Furthermore, Trask signaling and focal adhesion signaling inactivate each other and signal in exclusion with each other, constituting a switch that underlies cell anchorage state. These data provide considerable insight into how Trask functions to regulate cell adhesion and reveal a novel pathway through which Src kinases can oppose integrin-mediated cell adhesion.Src family kinases (SFKs) are a family of nonreceptor protein tyrosine kinases with a domain structure consisting of a highly conserved kinase domain as well as an SH2 domain and an SH3 domain, a C-terminal negative-regulatory tyrosine residue, and an N-terminal myristoylation site.
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