Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

c-Mil is the avian homologue of the mammalian serine/threonine kinase c-Raf-1. c-Mil/Raf is a mediator of signal transduction leading to gene expression via the c-Jun DNA-binding site, AP-1. Here we show that c-Mil immunopurified from MC29-virus-transformed quail fibroblasts phosphorylates c-Jun in vitro near its N terminus (Ser-63 and -73). Furthermore, the viral oncogene product Gag-Mil of the avian wild-type retrovirus MH2 phosphorylates c-Jun in vitro. A contribution by other known kinases phosphorylating c-Jun, such as the mitogen-activated protein kinases (MAPKs) and the c-Jun N-terminal kinases, was excluded by control reactions. c-Raf-1 and c-Jun directly interact in vitro as shown by various immobilized glutathione S-transferase-Raf fusion proteins which specify the cysteine-rich region of c-Mil/Raf as the major N-terminal binding site. An additional minor binding site is located in the C-terminal region. The biological relevance of these results is demonstrated by coimmunoprecipitation of c-Jun and c-Mil from 32P-labeled MC29- and MH2-transformed fibroblasts as well as normal quail embryo fibroblasts, whereby c-Jun was identified by tryptic phosphopeptide analysis. The complexed c-Jun exhibits a decreased electrophoretic mobility corresponding to a more highly phosphorylated state. Cell fractionation analyses indicate that the c-Mil/c-Jun complex is located in the cytoplasm. The data demonstrate that c-Jun can be a direct target of the protein kinase c-Mil/Raf, suggesting an alternative pathway, which leads to c-Jun phosphorylation independent of the MAPKs and MAPK-related proteins.
 ...
PMID:Direct interaction and N-terminal phosphorylation of c-Jun by c-Mil/Raf. 787 94

The c-Raf-1 protein kinase is a major element of several signal transduction pathways and thought to be involved in entry into the S phase of the cell cycle. Here we show that c-Raf-1 as well as the transforming viral fusion protein Gag-Mil, in which most of the amino terminal regulatory region of the avian Raf homologue Mil is deleted, are activated five- to sixfold in mitotic cells. Mitotic activation of Mil/Raf kinase activity correlates with reduced electrophoretic mobility caused by hyperphosphorylation at serine/threonine residues located in the carboxy terminal part of c-Raf-1. Mitotic hyperphosphorylation occurs in various cell-lines indicating that it is ubiquitous. Our data suggest a novel function for Mil/Raf kinases in late stages of the cell cycle.
 ...
PMID:Activation of Mil/Raf protein kinases in mitotic cells. 864 3