Network-based approaches for extending the Wnt signalling pathway and identifying context-specific sub-networks.

Wnt signalling is a critically important signalling pathway regulating embryogenesis and differentiation, and is broadly conserved amongst multicellular animals. In addition, dysregulation of Wnt signalling contributes to the pathogenesis of many human cancers, in particular colorectal cancer. Core members of the Wnt signalling pathway are quite well defined, although it has become apparent that a much broader network of interacting proteins regulates Wnt signalling activity.

DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination.

DNA methyltransferase 1 (DNMT1) is the primary enzyme that maintains DNA methylation. We describe a previously unknown mode of regulation of DNMT1 protein stability through the coordinated action of an array of DNMT1-associated proteins. DNMT1 was destabilized by acetylation by the acetyltransferase Tip60, which triggered ubiquitination by the E3 ligase UHRF1, thereby targeting DNMT1 for proteasomal degradation.

Multiple myeloma phosphotyrosine proteomic profile associated with FGFR3 expression, ligand activation, and drug inhibition.

Signaling by growth factor receptor tyrosine kinases is manifest through networks of proteins that are substrates and/or bind to the activated receptors. FGF receptor-3 (FGFR3) is a drug target in a subset of human multiple myelomas (MM) and is mutationally activated in some cervical and colon and many bladder cancers and in certain skeletal dysplasias. To define the FGFR3 network in multiple myeloma, mass spectrometry was used to identify and quantify phosphotyrosine (pY) sites modulated by FGFR3 activation and inhibition in myeloma-derived KMS11 cells.

Emerging applications for phospho-proteomics in cancer molecular therapeutics.

Protein phosphorylation is a key mechanism of cell regulation in normal and cancer cells. Various new cancer drugs and drug candidates are aimed at protein kinase targets. However, selecting patients likely to respond to these treatments, even among individuals with tumors expressing validated kinase targets remains a major challenge.