Regulation of ERK Signalling by the Scaffold Protein KSR1

Mammalian cells contain several signalling pathways that allow them to react to changes in their environment. One of the best-described signalling molecules is the Ras protein, a critical regulator of cellular proliferation, differentiation and survival in multicellular organisms. A major route by which Ras transmits cellular signals is through the sequential activation of the protein kinases Raf-1, MEK and ERK. Activation of this pathway often results in progression through the cell cycle and subsequent cellular proliferation. Because of its central role in growth regulation of mammalian cells, this pathway has to be precisely regulated and defects in its regulation have been attributed to many diseases, including cancer. Scaffold proteins provide spatial and temporal control to cellular signalling by directing associated proteins to specific compartments of the cell. In addition, they physically link several components of a pathway and can exclude others from the complex. In this proposal, we aim to characterise the role of the scaffold protein KSR1 in the regulation of ERK activity after growth factor stimulation of mammalian cells. These studies will provide new insight into the regulation of the ERK signal transduction pathway and will help to understand the processes that cause proliferative diseases like cancer.

The Ras GTPase is a critical regulator of cellular proliferation, differentiation and survival. A major route by which Ras transmits cellular signals is through the sequential activation of the protein kinases Raf-1, MEK and ERK. The outcome of signalling through this pathway is the translocation of activated ERK to the nucleus, where it phosphorylates a large number of proteins. This results in substantial changes in gene expression and ultimately progression through the G1 phase of the cell cycle.
Scaffold proteins provide spatial and temporal control to cellular signalling by directing associated proteins to specific compartments of the cell. In addition, they physically link several components of a pathway and can exclude others from the complex. Kinase Suppressor of Ras 1 (KSR1) is a conserved component of the Ras pathway that functions as a scaffold protein. It is dynamically regulated and has been found in the cytoplasm, at the plasma membrane, and in the nucleus. KSR1 enhances Ras signalling by linking Raf-1 and MEK at the plasma membrane, thereby facilitating the activation of MEK.
KSR1 also binds to activated ERK at the plasma membrane. However, the implications of this association for the signalling process are not well documented. In this proposal, we aim to characterise the role of the scaffold protein KSR1 in the regulation of ERK activity after growth factor stimulation of mammalian cells. These studies will provide new and substantial insight into the regulation of the MAPK signal transduction pathway. They will produce critical data regarding the regulation of ERK during mitogenic signalling and will emphasize the role of the scaffold protein KSR1 in this process.