Our mission is to understand 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 used expression cloning to isolate
proteins that interfere with ERK MAP kinase signaling to the cell
adhesion proteins the integrins. One such protein is PEA-15. PEA-15
can alter ERK signaling to other proteins as well, including the
transcription factor Elk1 and the kinase Rsk2.
PEA-15 is widely expressed throughout the body, with particularly
high levels expressed in astrocytes and lymphocytes. The
structure of PEA-15 is striking in that the N-terminal half
of the protein consists of a conserved death effector domain.
This domain is usually found in proteins involved in apoptosis.
Indeed, PEA-15 prevents FADD-mediated apoptosis. The C-terminal
half of the protein contains two phosphorylated serines that
appear to regulate PEA-15 function. Our work has shown that
PEA-15 binds directly to ERK and maintains it in the cytoplasm.
Similarly PEA-15 can also bind to Rsk2 and may therefore
affect ERK activation of Rsk2 in the cytoplasm. By determining
the location in the cell of these kinases PEA-15 can channel
ERK signaling to cytoplasmic substrates to the exclusion
of nuclear targets like the transcription factor ELK1 and
thus modify the outcome of ERK activation.
We are using PEA-15 null mice and molecular and cell biological
approaches to better understand the function of PEA-15. We
have also begun to isolate and characterize related proteins.
Because of the fundamental nature of this work it has applications
to a number of pathological states including cancer and diabetes.
Selected
Publications
H. Vaidyanathan, J. Opoku-Ansah, S. Pastorino, H. Renganathan, M.L.
Matter and J.W. Ramos. (2007). ERK MAP kinase is targeted to RSK2 by
the phosphoprotein PEA-15. PNAS, 105(50):19837-19842.
H. Renganathan, H. Vaidyanathan, A. Knapinska and J.W. Ramos. (2005).
Phosphorylation of PEA-15 Switches its Binding Specificity from ERK MAP
kinase to FADD. Biochem J., 390(3):729-735.
H. Vaidyanathan and J.W. Ramos. (2003). Rsk2 activity is regulated by its association with PEA-15. J. Biol. Chem. 278(34):32367-32372.
J.M. Hill, H. Vaidyanathan, J.W. Ramos, M.H. Ginsberg and M.H. Werner. (2002). Recognition of ERK MAP kinase by PEA-15 reveals a common docking site within the death domain and death effector domain. EMBO J 21(23):6494-6504.
M.L. Matter, M.H. Ginsberg, and J.W. Ramos. (2001). Identification of cell signaling molecules by expression cloning. Sci STKE. 2001 Oct 9;2001(103):PL9.
J.W. Ramos*, E. Formstecher*, M. Fauquet, D.A. Calderwood, J-C. Hsieh, B. Canton, X-T. Nguyen, J-V. Barnier, J. Camonis, M.H. Ginsberg, and H. Chneiweiss. (2001). PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Developmental Cell 1:239-250. *Co-first authors.
