scholarly journals The Caenorhabditis elegans EGL-15 Signaling Pathway Implicates a DOS-Like Multisubstrate Adaptor Protein in Fibroblast Growth Factor Signal Transduction

2001 ◽  
Vol 21 (23) ◽  
pp. 8104-8116 ◽  
Author(s):  
Jennifer L. Schutzman ◽  
Christina Z. Borland ◽  
John C. Newman ◽  
Matthew K. Robinson ◽  
Michelle Kokel ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Function Analysis ◽  
Adaptor Protein ◽  
Mitogen Activated Protein Kinase ◽  
Pleckstrin Homology Domain ◽  
Fibroblast Growth ◽  
Phenotypic Analysis ◽  
Amino Terminal

ABSTRACT EGL-15 is a fibroblast growth factor receptor in the nematodeCaenorhabditis elegans. Components that mediate EGL-15 signaling have been identified via mutations that confer a Clear (Clr) phenotype, indicative of hyperactivity of this pathway, or a suppressor-of-Clr (Soc) phenotype, indicative of reduced pathway activity. We have isolated a gain-of-function allele of let-60 ras that confers a Clr phenotype and implicated bothlet-60 ras and components of a mitogen-activated protein kinase cascade in EGL-15 signaling by their Soc phenotype. Epistasis analysis indicates that the gene soc-1 functions in EGL-15 signaling by acting either upstream of or independently of LET-60 RAS. soc-1 encodes a multisubstrate adaptor protein with an amino-terminal pleckstrin homology domain that is structurally similar to the DOS protein in Drosophilaand mammalian GAB1. DOS is known to act with the cytoplasmic tyrosine phosphatase Corkscrew (CSW) in signaling pathways inDrosophila. Similarly, the C. elegans CSW ortholog PTP-2 was found to be involved in EGL-15 signaling. Structure-function analysis of SOC-1 and phenotypic analysis of single and double mutants are consistent with a model in which SOC-1 and PTP-2 act together in a pathway downstream of EGL-15 and the Src homology domain 2 (SH2)/SH3-adaptor protein SEM-5/GRB2 contributes to SOC-1-independent activities of EGL-15.

scholarly journals A Novel Conserved Phosphotyrosine Motif in the Drosophila Fibroblast Growth Factor Signaling Adaptor Dof with a Redundant Role in Signal Transmission

2010 ◽  
Vol 30 (8) ◽  
pp. 2017-2027 ◽  
Author(s):  
Agnes Csiszar ◽  
Elisabeth Vogelsang ◽  
Hartmut Beug ◽  
Maria Leptin
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signal Transmission ◽  
Adaptor Protein ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Src Kinases ◽  
The Novel ◽  
Fibroblast Growth ◽  
Mapk Activation

ABSTRACT The fibroblast growth factor receptor (FGFR) signals through adaptors constitutively associated with the receptor. In Drosophila melanogaster, the FGFR-specific adaptor protein Downstream-of-FGFR (Dof) becomes phosphorylated upon receptor activation at several tyrosine residues, one of which recruits Corkscrew (Csw), the Drosophila homolog of SHP2, which provides a molecular link to mitogen-activated protein kinase (MAPK) activation. However, the Csw pathway is not the only link from Dof to MAPK. In this study, we identify a novel phosphotyrosine motif present in four copies in Dof and also found in other insect and vertebrate signaling molecules. We show that these motifs are phosphorylated and contribute to FGF signal transduction. They constitute one of three sets of phosphotyrosines that act redundantly in signal transmission: (i) a Csw binding site, (ii) four consensus Grb2 recognition sites, and (iii) four novel tyrosine motifs. We show that Src64B binds to Dof and that Src kinases contribute to FGFR-dependent MAPK activation. Phosphorylation of the novel tyrosine motifs is required for the interaction of Dof with Src64B. Thus, Src64B recruitment to Dof through the novel phosphosites can provide a new link to MAPK activation and other cellular responses. This may give a molecular explanation for the involvement of Src kinases in FGF-dependent developmental events.

scholarly journals The Docking Protein Gab1 Is an Essential Component of an Indirect Mechanism for Fibroblast Growth Factor Stimulation of the Phosphatidylinositol 3-Kinase/Akt Antiapoptotic Pathway

2004 ◽  
Vol 24 (13) ◽  
pp. 5657-5666 ◽  
Author(s):  
Betty Lamothe ◽  
Masashi Yamada ◽  
Ute Schaeper ◽  
Walter Birchmeier ◽  
Irit Lax ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Fibroblast Growth Factor ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Fibroblast Growth ◽  
Indirect Mechanism ◽  
Docking Protein ◽  
Stimulation Of

ABSTRACT The docking protein Gab1 has been implicated as a mediator of multiple signaling pathways that are activated by a variety of receptor tyrosine kinases and cytokines. We have previously proposed that fibroblast growth factor 1 (FGF1) stimulation of tyrosine phosphorylation of Gab1 and recruitment of phosphatidylinositol (PI) 3-kinase are mediated by an indirect mechanism in which the docking protein fibroblast receptor substrate 2α (FRS2α) plays a critical role. In this report, we explore the role of Gab1 in FGF1 signaling by using mouse embryo fibroblasts (MEFs) derived from Gab1−/− or FRS2α−/− mice. We demonstrate that Gab1 is essential for FGF1 stimulation of both PI 3-kinase and the antiapoptotic protein kinase Akt, while FGF1-induced mitogen-activated protein kinase (MAPK) stimulation is not affected by Gab1 deficiency. To test the indirect mechanism for FGF1 stimulation of PI 3-kinase and Akt, we use a chimeric docking protein composed of the membrane targeting signal and the phosphotyrosine-binding domain of FRS2α fused to the C-terminal portion of Gab1, the region including the binding sites for the complement of signaling proteins that are recruited by Gab1. We demonstrate that expression of the chimeric docking protein in Gab1−/− MEFs rescues PI 3-kinase and the Akt responses, while expression of the chimeric docking protein in FRS2α−/− MEFs rescues stimulation of both Akt and MAPK. These experiments underscore the essential role of Gab1 in FGF1 stimulation of the PI 3-kinase/Akt signaling pathway and provide further support for the indirect mechanism for FGF1 stimulation of PI 3-kinase involving regulated assembly of a multiprotein complex.

Functional components of basic fibroblast growth factor signaling that inhibit lung elastin gene expression

2001 ◽  
Vol 281 (4) ◽  
pp. L766-L775 ◽  
Author(s):  
Isabel Carreras ◽  
Celeste B. Rich ◽  
Julie A. Jaworski ◽  
Sandra J. Dicamillo ◽  
Mikhail P. Panchenko ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Fibroblast Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Activator Protein 1 ◽  
Fibroblast Growth ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Elastin Gene

Previously, we have demonstrated that basic fibroblast growth factor (bFGF) decreases elastin gene transcription in confluent rat lung fibroblasts via the binding of a Fra-1-c-Jun heterodimer to an activator protein-1-cAMP response element in the distal region of the elastin promoter. In the present study, we show that bFGF activates the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2, resulting in the translocation of phosphorylated extracellular signal-regulated kinase 1/2 into the nucleus followed by increased binding of Elk-1 to the serum response element of the c-Fos promoter, transient induction of c-Fos mRNA, and sustained induction of Fra-1 mRNA. The addition of PD-98059, an inhibitor of mitogen-activated protein kinase kinase, abrogates the bFGF-dependent repression of elastin mRNA expression. Comparative analyses of confluent and subconfluent fibroblast cultures reveal significant differences in elastin mRNA levels and activator protein-1 protein factors involved in the regulation of elastin transcription. These findings suggest that bFGF modulates specific cellular events that are dependent on the state of the cell and provide a rationale for the differential responses that can be expected in development and injury or repair situations.

scholarly journals Nuclear Activities of Basic Fibroblast Growth Factor: Potentiation of Low-Serum Growth Mediated by Natural or Chimeric Nuclear Localization Signals

1999 ◽  
Vol 10 (5) ◽  
pp. 1429-1444 ◽  
Author(s):  
Marco Arese ◽  
Yan Chen ◽  
Robert Z. Florkiewicz ◽  
Anna Gualandris ◽  
Bin Shen ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Serum Starvation ◽  
Fibroblast Growth ◽  
Stable Transfectants ◽  
Nuclear Localization Signals ◽  
Amino Terminal ◽  
Low Serum

Human basic fibroblast growth factor (FGF-2) occurs in four isoforms: a low molecular weight (LMW FGF-2, 18 kDa) and three high molecular weight (HMW FGF-2, 22, 22.5, and 24 kDa) forms. LMW FGF-2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF-2s are nuclear and exert activities through an intracrine, perhaps nuclear, pathway. Selective overexpression of HMW FGF-2 forms in fibroblasts promotes growth in low serum, whereas overexpression of LMW FGF-2 does not. The HMW FGF-2 forms have two functional domains: an amino-terminal extension and a common 18-kDa amino acid sequence. To investigate the role of these regions in the intracrine signaling of HMW FGF-2, we produced stable transfectants of NIH 3T3 fibroblasts overexpressing either individual HMW FGF-2 forms or artificially nuclear-targeted LMW FGF-2. All of these forms of FGF-2 localize to the nucleus/nucleolus and induce growth in low serum. The nuclear forms of FGF-2 trigger a mitogenic stimulus under serum starvation conditions and do not specifically protect the cells from apoptosis. These data indicate the existence of a specific role for nuclear FGF-2 and suggest that LMW FGF-2 represents the biological messenger in both the autocrine/paracrine and intracrine FGF-2 pathways.

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