Our research program focuses on two areas under the theme of cancer cell signaling and therapeutics. We emphasize an understanding of the cellular and biochemical properties of signaling proteins, to determine how they are regulated, how they perform their functions and as a basis for designing novel therapeutic strategies to target human cancers.
1) Molecular mechanisms of signal transduction. The altered regulation and function of signaling proteins, such as protein kinases, contribute to the ability of tumors to form and then to grow. Altered signaling also helps cancer cells to survive severe stresses that result from such things as poor oxygenation, altered metabolism and genetic instability. In addition, aberrant signaling allows cancer cells to avoid the immune system and promotes tumor metastasis. Our work aims to better understand how changes that may occur to alter a protein’s expression, regulation or sequence facilitate cancer phenotypes.
2) Novel strategies to inhibit aberrant signaling in cancer cells. Drug discovery projects in the laboratory focus on either unique targets or alternative approaches to inhibit validated targets. They may involve assay development, structure-guided chemical synthesis of lead compounds and target validation. Special emphasis is placed on potential mechanisms of resistance.
The mitogen-activated protein kinases (MAPKs)
The mitogen-activated protein kinases (MAPKs) are ubiquitous and highly conserved elements of signaling pathways that control many cellular events essential for life, ranging from cellular programs (in the form of differentiation, proliferation, and death, amongst others) to rapid changes required for vital hormonal responses and homeostasis.
To achieve their regulatory roles, the human MAPKs mediate networks of signal transduction cascades that negotiate cellular responses to a diverse range of stimuli, including growth factors, irradiation, pro-inflammatory cytokines, and stresses.
A huge amount of evidence shows the loss of MAPK regulation to be associated with many debilitating diseases, including nearly all cancers neurological diseases such as Alzheimer disease, and inflammatory diseases.
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Elongation Factor 2 kinase
Protein synthesis (translation) constitutes one of the most fundamental of all cellular processes. The balance between protein synthesis and protein degradation is critical in maintaining cellular homeostasis. Translation is one of the most energy consumptive processes in a cell, accounting for as much as 30% of the energy usage in a eukaryotic cell, making its tight regulation a necessity.
Eukaryotic elongation factor 2 kinase (eEF-2K), a member of the atypical-kinase family, is a key regulator of the elongation phase of translation. eEF-2K phosphorylates and inactivates elongation factor 2 (eEF-2), leading to a reduction in global translation rates on one hand and differential translation of certain proteins on the other.
The activity of eEF-2K is dependent on calmodulin, and is subject to complex regulation by calcium ions and phosphorylation. It may also have cellular substrates other than eEF-2.
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