University of Virginia Health System

Email Address: mjw@virginia.edu

MAP Kinase cascades are among the most thoroughly studied of signal transduction systems , and have been shown to participate in a diverse array of cellular programs including cell differentiation , cell movement , cell division and cell death. They typically are organized in a three-kinase architecture consisting of a MAP Kinase (MAPK) , a MAP Kinase activator (MEK) and a MEK activator (MEKK). Transmission of signals is achieved by sequential phosphorylation and activation of the components specific to a respective cascade. In mammalian systems five distinguishable MAP Kinase modules have been identified so far. These include the canonical ERK1/2 cascade that preferentially regulates cell growth and differentiation. Increased understanding of the ways these enzymes are regulated , targeted intracellularly and linked with other signaling pathways will enhance our insight into the regulatory networks that control cell behavior and provide clues as to how to exploit these as targets for therapy.

Signal transduction in human cancer.

Cancers undergo progressive changes that increase their malignant potential and thereby render them less susceptible to treatment. Analysis of the cellular signaling mechanisms that link the outside of the cancer cell to receptors and intracellular signal transduction cascades will provide insight into prevention , detection , and treatment strategies for cancer. Much of our recent efforts have been on elucidating the role of signal transduction in driving the progression of prostate cancer from an androgen-dependent disease to the frequently fatal androgen-independent disease. We currently are extending this work to include other cancers , including melanoma , bladder , and head and neck cancers , each of which provides unique opportunities to match knowledge about signaling with potential therapeutic interventions.