The Drosophila protein Dof is specifically required for FGF signaling.

Receptor tyrosine kinases (RTKs) transmit signals to the cell nucleus via the MAP kinase (MAPK) cascade, using specific molecules to link the activated receptors to the MAPK cascade activator, Ras. We have identified a component of the FGF receptor (FGFR) signal transduction pathway, Downstream of FGFR (Dof). Dof is an intracellular protein that is essential for signal transmission by the FGFR and acts downstream of the receptor and upstream of Ras. Unlike other signaling molecules that act downstream of RTKs, Dof is not expressed ubiquitously but is present exclusively in cells that express FGFRs. Dof is needed in these cells for activation of the MAPK cascade via FGF signaling, but not for activation via other RTK ligands. Dof therefore appears to be committed exclusively to FGFR-mediated signal transduction.

[1]  G. Rubin,et al.  The Ras signaling pathway in Drosophila. , 1995, Current opinion in genetics & development.

[2]  M. Bate,et al.  The development of Drosophila melanogaster , 1993 .

[3]  M. Goldfarb,et al.  Broadly expressed SNT-like proteins link FGF receptor stimulation to activators of Ras. , 1996, Oncogene.

[4]  T L Blundell,et al.  Fibroblast growth factor receptors: lessons from the genes. , 1998, Trends in biochemical sciences.

[5]  N. Hacohen,et al.  sprouty Encodes a Novel Antagonist of FGF Signaling that Patterns Apical Branching of the Drosophila Airways , 1998, Cell.

[6]  E. Hafen,et al.  DOS, a Novel Pleckstrin Homology Domain–Containing Protein Required for Signal Transduction between Sevenless and Ras1 in Drosophila , 1996, Cell.

[7]  Stephen S. Gisselbrecht,et al.  Dual functions of the heartless fibroblast growth factor receptor in development of the Drosophila embryonic mesoderm. , 1998, Developmental genetics.

[8]  Ernest D. Laue,et al.  Structure of the cyclin-dependent kinase inhibitor p19Ink4d , 1997, Nature.

[9]  Stephen S. Gisselbrecht,et al.  heartless encodes a fibroblast growth factor receptor (DFR1/DFGF-R2) involved in the directional migration of early mesodermal cells in the Drosophila embryo. , 1996, Genes & development.

[10]  B. Zetter,et al.  Angiogenesis and tumor metastasis. , 1998, Annual review of medicine.

[11]  D Cowburn,et al.  Modular peptide recognition domains in eukaryotic signaling. , 1997, Annual review of biophysics and biomolecular structure.

[12]  D. Donoghue,et al.  FGFR activation in skeletal disorders: too much of a good thing. , 1997, Trends in genetics : TIG.

[13]  B. Shilo,et al.  MAP kinase in situ activation atlas during Drosophila embryogenesis. , 1997, Development.

[14]  A. Lupas.  Prediction and analysis of coiled-coil structures. , 1996, Methods in enzymology.

[15]  D. Bar-Sagi,et al.  A Lipid-Anchored Grb2-Binding Protein That Links FGF-Receptor Activation to the Ras/MAPK Signaling Pathway , 1997, Cell.

[16]  B. Shilo,et al.  In situ activation pattern of Drosophila EGF receptor pathway during development. , 1997, Science.

[17]  David A. Cheresh,et al.  Regulation of Cell Motility by Mitogen-activated Protein Kinase , 1997, The Journal of cell biology.

[18]  N. Pavletich,et al.  Structure of the p53 Tumor Suppressor Bound to the Ankyrin and SH3 Domains of 53BP2 , 1996, Science.

[19]  M. Krasnow,et al.  branchless Encodes a Drosophila FGF Homolog That Controls Tracheal Cell Migration and the Pattern of Branching , 1996, Cell.

[20]  M. Wasser,et al.  A basic-helix-loop-helix protein expressed in precursors of Drosophila longitudinal visceral muscles , 1997, Mechanisms of Development.

[21]  K. Saigo,et al.  Requirements of DFR1/Heartless, a mesoderm-specific Drosophila FGF-receptor, for the formation of heart, visceral and somatic muscles, and ensheathing of longitudinal axon tracts in CNS. , 1997, Development.

[22]  B. Shilo,et al.  Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages. , 1996, Genes & development.

[23]  A. Spradling,et al.  Analysis of subtelomeric heterochromatin in the Drosophila minichromosome Dp1187 by single P element insertional mutagenesis. , 1992, Genetics.

[24]  E. Hafen,et al.  The pruned gene encodes the Drosophila serum response factor and regulates cytoplasmic outgrowth during terminal branching of the tracheal system. , 1996, Development.

[25]  J. Schlessinger.  SH2/SH3 signaling proteins. , 1994, Current opinion in genetics & development.

[26]  R. Schuh,et al.  Dual function of the region-specific homeotic gene spalt during Drosophila tracheal system development. , 1996, Development.

[27]  E. Hafen,et al.  Elucidation of the role of breathless, a Drosophila FGF receptor homolog, in tracheal cell migration. , 1994, Genes & development.

[28]  H. Rubinfeld,et al.  Detection of ERK activation by a novel monoclonal antibody , 1997, FEBS letters.

[29]  Thomas C. Kaufman,et al.  brahma: A regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2 SWI2 , 1992, Cell.

[30]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[31]  M. Ashburner,et al.  P-element insertion alleles of essential genes on the third chromosome of Drosophila melanogaster: correlation of physical and cytogenetic maps in chromosomal region 86E-87F. , 1997, Genetics.

[32]  M. Krasnow,et al.  The Drosophila Serum Response Factor gene is required for the formation of intervein tissue of the wing and is allelic to blistered. , 1996, Development.

[33]  N. Perrimon,et al.  Control of cell fate determination by p21ras/Ras1, an essential component of torso signaling in Drosophila. , 1993, Genes & development.

[34]  H. Jäckle,et al.  The Drosophila fork head domain protein crocodile is required for the establishment of head structures. , 1995, EMBO Journal.

[35]  B. Shilo,et al.  breathless, a Drosophila FGF receptor homolog, is essential for migration of tracheal and specific midline glial cells. , 1992, Genes & development.

[36]  N. Hacohen,et al.  Regulated Breathless receptor tyrosine kinase activity required to pattern cell migration and branching in the Drosophila tracheal system. , 1996, Genes & development.

[37]  P. Carroll,et al.  Daughter of Sevenless Is a Substrate of the Phosphotyrosine Phosphatase Corkscrew and Functions during Sevenless Signaling , 1996, Cell.

[38]  S. Mackem,et al.  Soluble dominant‐negative receptor uncovers essential roles for fibroblast growth factors in multi‐organ induction and patterning , 1998, The EMBO journal.

[39]  Tony Pawson,et al.  Protein modules and signalling networks , 1995, Nature.

[40]  G. Rubin,et al.  Signalling by the sevenless protein tyrosine kinase is mimicked by Rasl activation , 1992, Nature.

[41]  F. Kafatos,et al.  Functional cDNA libraries from Drosophila embryos. , 1988, Journal of molecular biology.

[42]  M. Leptin,et al.  Identification of novel genes in Drosophila reveals the complex regulation of early gene activity in the mesoderm. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Kanda,et al.  Shc and a Novel 89-kDa Component Couple to the Grb2-Sos Complex in Fibroblast Growth Factor-2-stimulated Cells (*) , 1995, The Journal of Biological Chemistry.

[44]  E. Hafen,et al.  Raf functions downstream of Rasl in the Sevenless signal transduction pathway , 1992, Nature.

[45]  Cynthia Wolberger,et al.  The Structure of GABPα/β: An ETS Domain- Ankyrin Repeat Heterodimer Bound to DNA , 1998 .

[46]  S. Hayashi,et al.  A nuclear GFP/β‐galactosidase fusion protein as a marker for morphogenesis in living Drosophila , 1996 .