Programmed cell death (PCD) is an important biological process used developmentally by multi-cellular organisms to pattern tissue structures and post-developmentally as a means to maintain homeostasis. Disruption of programmed cell death signaling post-developmentally contributes to human diseases ranging from cancer initiation and progression to neurodegenerative diseases.
PCD is utilized as a means to eradicate damaged precancerous cells to prevent tumor formation. Mutations that impair PCD processes create a cellular state in which precancerous cells are not destroyed allowing them to proliferate and progress to a cancerous state. As a result of this, the elucidation of PCD pathways has become a major goal of cancer research with the hope of identifying therapeutic targets for small molecules to activate PCD in cancer cells.
Activation of PCD has been linked to the neuronal cell death that is observed in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington’s disease (HD). The etiology of non-familial forms of these neurodegenerative diseases is largely unknown, but it is speculated that the mechanisms that lead to the ultimate death of neurons in these diseases is similar. A common theme in neurodegenerative diseases is mitochondrial dysfunction and oxidative stress leading to neuron loss through PCD. Because of this, there is great interest in defining PCD signaling mechanisms with the goal of developing strategies to rescue neurons from PCD fates and prolong their lives.
While it may seem that cancer and neurodegeneration are unrelated problems, recent findings by our lab and others have determined that axon guidance receptor signaling plays a role in both of these types of human disease in addition to their classical roles in nervous system patterning. Using Drosophila as a model organism, our studies have identified a link between the Netrin binding axon guidance receptors and the anti-apoptotic properties of Activated cdc42 kinase (Ack). The Ack family comprises structurally related non-receptor tyrosine kinases that are evolutionarily conserved from worms to humans. Activating mutations in Ack1 and increased Ack1 protein levels have been found in many human cancers, where their presence correlates with a poor prognosis. In spite of these findings, it is unclear what the physiological functions of Ack are.
Our current focus is in defining the signaling pathways and molecular mechanisms that converge upon Ack to control PCD from both a cancer and neurodegenerative perspective. To accomplish these goals, we combine biochemical, molecular biological and molecular genetic approaches within the Drosophila system.