Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase

A signaling pathway has been elucidated whereby growth factors activate the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB), a critical regulator of immediate early gene transcription. Growth factor-stimulated CREB phosphorylation at serine-133 is mediated by the RAS-mitogen-activated protein kinase (MAPK) pathway. MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90RSK family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression.

[1]  C. Marshall,et al.  MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. , 1994, Current opinion in genetics & development.

[2]  J. Blenis,et al.  Signal transduction via the MAP kinases: proceed at your own RSK. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Philip R. Cohen,et al.  Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rskmo-2. Identification of two threonines phosphorylated during activation by mitogen-activated protein kinase. , 1993, European journal of biochemistry.

[4]  E. Krebs,et al.  Overexpression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH 3T3 cells. Evidence that MAPKK involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII. , 1994, The Journal of biological chemistry.

[5]  J. Maller,et al.  Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II , 1988, Nature.

[6]  E. Van Obberghen,et al.  Nerve growth factor-induced phosphorylation cascade in PC12 pheochromocytoma cells. Association of S6 kinase II with the microtubule-associated protein kinase, ERK1. , 1992, The Journal of biological chemistry.

[7]  M E Greenberg,et al.  Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. , 1993, Science.

[8]  S. Weremowicz,et al.  RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation , 1995, Molecular and cellular biology.

[9]  J. Ferrell,et al.  Evidence that inactive p42 mitogen-activated protein kinase and inactive Rsk exist as a heterodimer in vivo. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Hong Sun,et al.  MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo , 1993, Cell.

[11]  E. Krebs,et al.  The MAPK signaling cascade , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  M. Greenberg,et al.  Intracellular signaling pathways activated by neurotrophic factors. , 1996, Annual review of neuroscience.

[13]  J. Blenis,et al.  Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Nordheim,et al.  Activation of ternary complex factor Elk‐1 by MAP kinases. , 1993, The EMBO journal.

[15]  R. Treisman,et al.  The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain , 1993, Cell.

[16]  J. Blenis,et al.  A Xenopus ribosomal protein S6 kinase has two apparent kinase domains that are each similar to distinct protein kinases. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Greenberg,et al.  A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity , 1993, Molecular and cellular biology.

[18]  J. Blenis,et al.  Mitogen-activated Swiss mouse 3T3 RSK kinases I and II are related to pp44mpk from sea star oocytes and participate in the regulation of pp90rsk activity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Greenberg,et al.  Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB , 1994, Cell.

[20]  D. Moller,et al.  Human rsk isoforms: cloning and characterization of tissue-specific expression. , 1994, The American journal of physiology.

[21]  M. Gilman,et al.  Two distinct forms of active transcription factor CREB (cAMP response element binding protein). , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Richard J Smeyne,et al.  Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements , 1995, Neuron.

[23]  J. Avruch,et al.  Regulation of an epitope-tagged recombinant Rsk-1 S6 kinase by phorbol ester and erk/MAP kinase. , 1993, Biochemistry.

[24]  K. Riabowol,et al.  Multiple sequence elements of a single functional class are required for cyclic AMP responsiveness of the mouse c-fos promoter , 1989, Molecular and cellular biology.

[25]  H. Herschman.  Primary response genes induced by growth factors and tumor promoters. , 1991, Annual review of biochemistry.

[26]  Hong Sun,et al.  The growth factor-inducible immediate-early gene 3CH134 encodes a protein-tyrosine-phosphatase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Treisman.  Ternary complex factors: growth factor regulated transcriptional activators. , 1994, Current opinion in genetics & development.

[28]  J. Blenis,et al.  Nuclear localization and regulation of erk- and rsk-encoded protein kinases , 1992, Molecular and cellular biology.

[29]  M. Greenberg,et al.  Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca2+/calmodulin-dependent kinase , 1995, Molecular and cellular biology.

[30]  A. Sharrocks,et al.  Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter , 1992, Nature.

[31]  M. Greenberg,et al.  Serine 133-Phosphorylated CREB Induces Transcription via a Cooperative Mechanism That May Confer Specificity to Neurotrophin Signals , 1995, Molecular and Cellular Neuroscience.

[32]  D. Alcorta,et al.  Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase , 1989, Molecular and cellular biology.

[33]  Mark I. Greene,et al.  Control of MHC Restriction by TCR Vα CDR1 and CDR2 , 1996, Science.

[34]  T. Hansen,et al.  Cloning of a Human Insulin-Stimulated Protein Kinase (ISPK-1) Gene and Analysis of Coding Regions and mRNA Levels of the ISPK-1 and the Protein Phosphatase-1 Genes in Muscle From NIDDM Patients , 1995, Diabetes.