The mitogen-activated protein kinases (MAPKs) are a superfamily of highly homologous proline-directed serine/threonine kinases that participate in the transduction of growth and differentiation-promoting signals, as well as stress responses to the cell nucleus. The presence of at least six MAP kinases in yeast suggests that there are likely to more in mammals. In order to detect additional MAP kinases, we screened a rat brain library using degenerate polymerase chain reaction (PCR) and identified a novel MAPK termed ERK7 that encodes a 61 kD, 546 amino- acid long protein ERK7 contains the Thr-Glu-Tyr (TEY) activation motif characteristics of other ERKs, but has a number of properties that are unique. ERK7 has a discrete C-terminal domain that contains SH3 binding motifs. Unlike other ERKs, ERK7 has significant constitutive kinase activity, and this activity is dependent upon the C-terminal domain. Furthermore, ERK7's C-terminal domain rather than its kinase activity is required for nuclear localization and its function as an inhibitor of DNA synthesis. Finally, ERK7 is the first MAP kinase that has been found to specifically associate with a protein that activates chloride ion transport, CLIC3, and the C-terminal domain is sufficient for CLIC3 binding. The identification of a MAPK with C-terminal SH3-binding domains and the importance of the C-terminus in ERK7 function suggests that ERK7 represents a subfamily of MAPKs with adaptor domains that contribute to signaling specificity in growth and development. In this application, we propose to further characterize the regulation and function of this novel kinase. Specifically, we plan to use molecular and cellular approaches to 1) Determine the mechanism by which ERK7 is activated; 2) Identify key functional domains, binding partners and potential substrates of ERK7; and 3) Investigate the function of ERK7 in cell and tissues. The results of these studies will test the hypothesis that ERK7, like other ERKs, play a key role in the regulation of cell growth and tumor progression, and will increase our understanding of this new member of the MAPK family.

R01GM061038

2001-02-01

2006-01-31