MAY 29, 2014 12:00 PM PDT

Navigating the Complexities of the Human Oncoproteome with the SigNET KnowledgeBank

Speakers
  • Professor, Department of Medicine, University of British Columbia, President & Chief Scientific Officer, Kinexus Bioinformatics Corporation
    Biography
      Dr. Steven Pelech has been the founder, president and chief scientific officer of Kinexus Bioinformatics Corporation for 15 years. He was previously the founder and president of Kinetek Pharmaceuticals, Inc. for 6 years. Prior to this, he spent 5 years in post-doctoral training with Sir Philip Cohen at the University of Dundee and Nobel laureate Dr. Edwin Krebs at the University of Washington in Seattle. Dr. Pelech was a founding scientist of the Biomedical Research Centre and of the Brain Research Centre located at the University of British Columbia (UBC). Since 1988, he has concurrently been on faculty at UBC and is presently a full professor in the Department of Medicine in the Division of Neurology. Dr. Pelech received his B.Sc. (1979; Honours) and Ph.D. (1982) degrees in Biochemistry from UBC. He has authored over 220 scientific peer- reviewed publications about signal transduction and is one of the discoverers of the MAP kinases. His recent focus has been on the development of a suite of open-access, on-line KiNET databases and SigNET knowledgebases, and on the creation of high content array platforms with antibodies and peptides to support systems proteomics research. He has served on grant review panels and as an ad-hoc reviewer for over 30 granting agencies and as an external reviewer for over 30 scientific journals.

    Abstract:

    The human genome encodes ~21,500 proteins that are subject to reversible phosphorylation at nearly 1 million phosphosites by about 538 protein kinases and 156 protein phosphatases. Amongst other regulatory proteins, these classes of proteins play a central role in cancer as oncoproteins (OP), tumour-requiring proteins (TRP) or tumour suppressor proteins (TSP). They can be distinguished in part by their mutation patterns across thousands of tumour specimens. OP feature highly restricted mutations that produce a gain of function, commonly by loss of repression by inhibitory domains or mimicry of activating phosphorylation sites with acid amino acid residue substitutions. TSP typically feature an extensive range of mutation types and locations in their genes, which lead to their loss of function. By contrast, TRP display extremely low rates of mutation in human cancers, about 5 to 10-fold lower that the background mutation rates evident in bystander genes. TRP may serve as ideal targets for cancer drug development as they may be more commonly required for cancer development than OP, and they may be less tolerant to mutations that facilitate drug resistance. Interestingly, many OP are down-regulated and TSP are up-regulated in their protein levels in human tumours, which indicates that intracellular regulatory networks typically evoke compensatory mechanisms to restore growth control or induce apoptosis. Therefore, gene expression and mutation data has to be interpreted in the context of integrated signalling pathways. The open-access, on-line suite of SigNET KnowledgeBases offered by Kinexus provide extensive known and predictive information of human proteins, their gene expression, interactions and phosphorylation, and in the case of protein kinases, drug interactions. The new OncoNET website (www.onconet.ca) is a repository of detailed information about the mRNA expression and mutation patterns for nearly 3000 genes linked to diverse types of human cancers.


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