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Transcriptional regulation by MAP kinases
1Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, University of Massachusetts Medical Center, Worcester, MA 01605, USA.
Abstract:
Tyrosine kinase growth factor receptors activate MAP kinase by a complex mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP kinase. Subsequently, the activated MAP kinase translocates into the nucleus where many of the physiological targets of the MAP kinase signal transduction pathway are located. These substrates include transcription factors that are regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of signal transduction by growth factor receptors from the cell surface to the nucleus that results in the regulation of gene expression. Three MAP kinase homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP kinases that are similar to the rat Erk kinases have also been identified by molecular cloning. The human Erk1 protein kinase has been shown to be widely expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is a 41-kDa protein that is expressed ubiquitously. In contrast, a human Erk3-related protein kinase has been found to be expressed at a high level only in heart muscle and brain. The loci of these MAP kinase genes are widely distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together, these kinases are a more diverse group than the human erks that have been identified. Thus the erks are likely to represent only one subgroup of a larger human MAP kinase gene family. A candidate for this extended family of MAP kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative of the MAP kinase group that is activated by dual phosphorylation at Tyr and Thr.
Insights
The mitogen-activated protein (MAP) kinase pathway transmits signals from growth factor receptors to the nucleus, regulating gene expression. This pathway involves key proteins like Ras and Raf, leading to MAP kinase activation and nuclear translocation to modify transcription factors.
Area of Science:
- Molecular Biology
- Cell Signaling
- Genetics
Background:
- Growth factor receptors initiate intracellular signaling cascades.
- The mitogen-activated protein (MAP) kinase pathway is crucial for cellular responses to external stimuli.
- This pathway links cell surface receptors to nuclear gene expression regulation.
Purpose of the Study:
- To elucidate the mechanism of MAP kinase activation by growth factor receptors.
- To identify and characterize MAP kinase homologs in humans and yeast.
- To explore the diversity and evolutionary relationships within the MAP kinase gene family.
Main Methods:
- Investigated the role of Grb2, Sos, and Ras in MAP kinase activation.
- Identified and cloned human MAP kinase homologs (Erk1, Erk2, Erk3).
- Analyzed gene loci and expression patterns of human MAP kinases.
- Compared human MAP kinases with homologs in Saccharomyces cerevisiae.
- Examined the relationship between c-Jun NH2-terminal kinase (Jnk) and MAP kinases.
Main Results:
- MAP kinase activation involves a cascade initiated by Ras binding to Raf kinase.
- Human MAP kinases Erk1 and Erk2 are widely expressed, while Erk3 is primarily in heart and brain.
- Human MAP kinase genes (erk1, erk2, erk3-related) are located on different chromosomes.
- Yeast harbors a more diverse set of MAP kinase homologs than currently identified human Erks.
- Jnk is identified as a distant relative of MAP kinases, activated by dual phosphorylation.
Conclusions:
- The MAP kinase pathway is a significant signal transduction mechanism from cell surface to nucleus.
- Human MAP kinases represent a subgroup of a larger, more diverse gene family.
- Further research is needed to fully understand the extended MAP kinase family and their functions.