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.

scholarly journals The Docking Protein FRS2α Is an Essential Component of Multiple Fibroblast Growth Factor Responses during Early Mouse Development

2005 ◽  
Vol 25 (10) ◽  
pp. 4105-4116 ◽  
Author(s):  
N. Gotoh ◽  
K. Manova ◽  
S. Tanaka ◽  
M. Murohashi ◽  
Y. Hadari ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Critical Role ◽  
Physiological Role ◽  
Mitogen Activated Protein Kinase ◽  
Null Mouse ◽  
Fibroblast Growth ◽  
Mouse Development ◽  
Docking Protein

ABSTRACT The docking protein FRS2α is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2α in vivo remains unknown. In this report, we show that Frs2α-null mouse embryos have a defect in anterior-posterior (A-P) axis formation and are developmentally retarded, resulting in embryonic lethality by embryonic day 8. We demonstrate that FRS2α is essential for the maintenance of self-renewing trophoblast stem (TS) cells in response to FGF4 in the extraembryonic ectoderm (ExE) that gives rise to tissues of the placenta. By analyzing chimeric embryos, we found that FRS2α also plays a role in cell movement through the primitive streak during gastrulation. In addition, experiments are presented demonstrating that Bmp4 expression in TS cells is controlled by mitogen-activated protein kinase-dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smad1/5 in epiblasts are reduced in Frs2α-null embryos. These experiments underscore the critical role of FRS2α in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.

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.

Stimulatory Effect of Basic Fibroblast Growth Factor on Induction of Heat Shock Protein 27 in Osteoblasts: Role of Protein Kinase C

2001 ◽  
Vol 388 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Hiroyuki Matsuno ◽  
Akira Ishisaki ◽  
Kanefusa Kato ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Heat Shock ◽  
Protein Kinase ◽  
Heat Shock Protein ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Fibroblast Growth ◽  
Kinase C
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