We are investigating the regulation of the MAP kinase pathway.  In particular, we have focused on how activation of this ubiquitous pathway can give rise to different outcomes in different cells.  As a first step in this work, we have used expression cloning to isolate proteins that interfere with an ERK MAP kinase signal to integrins.  Integrins are transmembrane heterodimers that mediate cell-cell and cell-extracellular matrix adhesion.  Activation of H-Ras, or its effector kinase, c-Raf-1, initiates a signaling pathway that impairs integrin ligand-binding.  This suppressor activity correlates with the activation of the ERK MAP kinase pathway. These changes in integrin activation may affect cell morphology, adhesion, and invasiveness. We used the H-Ras to integrin pathway as a tool to discover proteins that suppress ERK MAP kinase signaling.  One such protein is PEA-15. Several recent observations suggest that PEA-15 can affect ERK signaling to other proteins as well, including the transcription factor Elk1. 

PEA-15 is widely expressed throughout the body, with particularly high levels expressed in astrocytes.  The structure of PEA-15 is striking in that the N-terminal half of the protein consists of a conserved death effector domain (DED).  This domain, to date, is associated only with proteins involved in apoptosis. Indeed, PEA-15 prevents FADD-mediated apoptosis.  Moreover, the DED of PEA-15 is necessary, but not sufficient for PEA-15 blockage of the Ras to integrin signal.

We are using PEA-15 null mice and molecular and cell biological approaches to better understand the function of PEA-15 and its role in the development of cancers, including Breast cancer and Leukemia.

© 2006, Joe W. Ramos