Extracellular signal-regulated kinases

Main article: Mitogen-activated protein kinase

In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules which are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.^{[citation needed]}

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The term, "extracellular signal-regulated kinases", is sometimes used as a synonym for mitogen-activated protein kinase (MAPK), but has more recently been adopted for a specific subset of the mammalian MAPK family. In the MAPK/ERK pathway, Ras activates c-Raf, followed by MEK and then MAPK1/2 (below). Ras is typically activated by growth hormones through receptor tyrosine kinases and GRB2/SOS, but may also receive other signals. ERKs are known to activate many transcription factors and some downstream protein kinases. Disruption of the ERK pathway is common in cancers, especially Ras, c-Raf and receptors such as HER2.

Mitogen-activated protein kinase 1

The molecular events linking cell surface receptors to activation of ERKs are complex. It was found that Ras GTP-binding proteins are involved in the activation of ERKs.^[2] Another protein kinase, Raf-1, was shown to phosphorylate a "MAPK kinase", thus qualifying as a "MAPK kinase kinase".^[3] The MAPK kinase was named "MAPK/ERK kinase" (MEK).^[4]

Receptor-linked tyrosine kinases, Ras, Raf, MEK and MAPK could be fitted into a signaling cascade linking an extracellular signal to MAPK activation.^[5] See: MAPK/ERK pathway.

Transgenic gene knockout mice lacking MAPK1 have major defects in early development.^[6]

Mitogen-activated protein kinase 3

References

1. ^ T. G. Boulton and M. H. Cobb (1991) "Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies" in Cell Regulation Volume 2, pages 357-571. Entrez PubMed 1654126.
2. ^ S. J. Leevers and C. J. Marshall (1992) "Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein" in The EMBO Journal Volume 11, page 569-574. Entrez PubMed 1371463.
3. ^ J. M. Kyriakis, H. App, X. F. Zhang, P. Banerjee, D. L. Brautigan, U. R. Rapp and J. Avruch (1992) "Raf-1 activates MAP kinase-kinase" in Nature Volume 358, pages 417-421.Entrez PubMed 1322500.
4. ^ C. M. Crews and R. L. Erikson (1992) "Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product" in Proceedings of the National Academy of Sciences of the United States of America Volume 89, pages 8205-8209. Entrez PubMed 1381507.
5. ^ T. Itoh, K. Kaibuchi, T. Masuda, T. Yamamoto, Y. Matsuura, A. Maeda, K. Shimizu and Y. Takai (1993) "A protein factor for ras p21-dependent activation of mitogen-activated protein (MAP) kinase through MAP kinase kinase" in Proceedings of the National Academy of Sciences of the United States of America Volume 90, pages 975-979. Entrez PubMed 8381539.
6. ^ Y. Yao W. Li, J. Wu, U. A. Germann, M. S. Su, K. Kuida and D. M. Boucher (2003) "Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation" in Proceedings of the National Academy of Sciences of the United States of America Volume 100, pages 12759-12764. Entrez PubMed 14566055.
7. ^ G. Pages, S. Guerin, D. Grall, F. Bonino, A. Smith, F. Anjuere P. Auberger and J. Pouyssegur (1999) "Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice" in Science Volume 286, pages 1374-1377. Entrez PubMed 10558995.