scholarly journals Zebrafish Mesp family genes, mesp-a and mesp-b are segmentally expressed in the presomitic mesoderm, and Mesp-b confers the anterior identity to the developing somites

Development ◽  
2000 ◽  
Vol 127 (8) ◽  
pp. 1691-1702 ◽  
Author(s):  
A. Sawada ◽  
A. Fritz ◽  
Y. Jiang ◽  
A. Yamamoto ◽  
K. Yamasu ◽  
...  
Keyword(s):  
Fibroblast Growth Factor Receptor ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Paraxial Mesoderm ◽  
Signalling Pathways ◽  
Fibroblast Growth ◽  
Presomitic Mesoderm ◽  
Receptor Signalling ◽  
Vertebrate Embryo ◽  
Bhlh Transcription Factors

Segmentation of a vertebrate embryo begins with the subdivision of the paraxial mesoderm into somites through a not-well-understood process. Recent studies provided evidence that the Notch-Delta and the FGFR (fibroblast growth factor receptor) signalling pathways are required for segmentation. In addition, the Mesp family of bHLH transcription factors have been implicated in establishing a segmental prepattern in the presomitic mesoderm. In this study, we have characterized zebrafish mesp-a and mesp-b genes that are closely related to Mesp family genes in other vertebrates. During gastrulation, only mesp-a is expressed in the paraxial mesoderm at the blastoderm margin. During the segmentation period, both genes are segmentally expressed in one to three stripes in the anterior parts of somite primordia. In fused somites (fss) embryos, in which all early somite boundary formation is blocked, initial mesp-a expression at the gastrula stage remains intact, but the expression of mesp-a and mesp-b is not detected during the segmentation period. This suggests that these genes are downstream targets of fss at the segmentation stage. Comparison with her1 expression (Muller, M., von Weizsacker, E. and Campos-Ortega, J. A. (1996) Development 122, 2071–2078) suggests that, like her1, mesp genes are not expressed in primordia of the first several somites. Furthermore, we found that zebrafish her1 expression oscillates in the presomitic mesoderm. The her1 stripe, which first appears in the tailbud region, moves in a caudal to rostral direction, and it finally overlaps the most rostral mesp stripe. Thus, in the trunk region, both her1 and mesp transcripts are detected in every somite primordium posterior to the forming somites. Ectopic expression of Mesp-b in embryos causes a loss of the posterior identity within the somite primordium, leading to a segmentation defect. These embryos show a reduction in expression of the posterior genes, myoD and notch5, with uniform expression of the anterior genes, FGFR1, papc and notch6. These observations suggest that zebrafish mesp genes are involved in anteroposterior specification within the presumptive somites, by regulating the essential signalling pathways mediated by Notch-Delta and FGFR.

Indirect recruitment of the signalling adaptor Shc to the fibroblast growth factor receptor 2 (FGFR2)

2008 ◽  
Vol 416 (2) ◽  
pp. 189-199 ◽  
Author(s):  
Annika C. Schüller ◽  
Zamal Ahmed ◽  
James A. Levitt ◽  
Kin M. Suen ◽  
Klaus Suhling ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Signalling Pathways ◽  
Fibroblast Growth ◽  
Src Homology ◽  
Receptor Family ◽  
Ptb Domain

The adaptor protein Shc (Src homology and collagen-containing protein) plays an important role in the activation of signalling pathways downstream of RTKs (receptor tyrosine kinases) regulating diverse cellular functions, such as differentiation, adhesion, migration and mitogenesis. Despite being phosphorylated downstream of members of the FGFR (fibroblast growth factor receptor) family, a direct interaction of Shc with this receptor family has not been described to date. Various studies have suggested potential binding sites for the Shc PTB domain (phosphotyrosine-binding domain) and/or the SH2 (Src homology 2) domain on FGFR1, but no interaction of full-length Shc with these sites has been reported in vivo. In the present study, we investigated the importance of the SH2 domain and the PTB domain in recruitment of Shc to FGFR2(IIIc) to characterize the interaction of these two proteins. Confocal microscopy revealed extensive co-localization of Shc with FGFR2. The PTB domain was identified as the critical component of Shc which mediates membrane localization. Results from FLIM (fluorescence lifetime imaging microscopy) revealed that the interaction between Shc and FGFR2 is indirect, suggesting that the adaptor protein forms part of a signalling complex containing the receptor. We identified the non-RTK Src as a protein which potentially mediates the formation of such a ternary complex. Although an interaction between Src and Shc has been described previously, in the present study we implicate the Shc SH2 domain as a novel mediator of this association. The recruitment of Shc to FGFR2 via an indirect mechanism provides new insight into the regulation of protein assembly and activation of various signalling pathways downstream of this RTK.

Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 992-998 ◽  
Author(s):  
Elizabeth E. Plowright ◽  
Zhihua Li ◽  
P. Leif Bergsagel ◽  
Marta Chesi ◽  
Dwayne L. Barber ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Messenger Rna ◽  
Fibroblast Growth Factor Receptor ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Growth Factor Receptor ◽  
Myeloma Cell ◽  
Fibroblast Growth ◽  
Wild Type

The t(4;14) translocation occurs in 25% of multiple myeloma (MM) and results in both the ectopic expression of fibroblast growth factor receptor 3 (FGFR3) from der4 and immunoglobulin heavy chain-MMSET hybrid messenger RNA transcripts from der14. The subsequent selection of activating mutations of the translocated FGFR3 by MM cells indicates an important role for this signaling pathway in tumor development and progression. To investigate the mechanism by which FGFR3 overexpression promotes MM development, interleukin-6 (IL-6)-dependent murine B9 cells were transduced with retroviruses expressing functional wild-type or constitutively activated mutant FGFR3. Overexpression of mutant FGFR3 resulted in IL-6 independence, decreased apoptosis, and an enhanced proliferative response to IL-6. In the presence of ligand, wild-type FGFR3-expressing cells also exhibited enhanced proliferation and survival in comparison to controls. B9 clones expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed increased phosphorylation of STAT3 and higher levels of bcl-xL expression than did parental B9 cells after cytokine withdrawal. The mechanism of the enhanced cell responsiveness to IL-6 is unknown at this time, but does not appear to be mediated by the mitogen-activated protein kinases SAPK, p38, or ERK. These findings provide a rational explanation for the mechanism by which FGFR3 contributes to both the viability and propagation of the myeloma clone and provide a basis for the development of therapies targeting this pathway.

scholarly journals Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8

2012 ◽  
Vol 126 (2) ◽  
pp. 613-624 ◽  
Author(s):  
G. Auciello ◽  
D. L. Cunningham ◽  
T. Tatar ◽  
J. K. Heath ◽  
J. Z. Rappoport
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Receptor Signalling

FGFR3 targeting strategies for achondroplasia

2012 ◽  
Vol 14 ◽  
Author(s):  
Melanie B. Laederich ◽  
William A. Horton
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Therapeutic Strategies ◽  
Signalling Pathways ◽  
Fibroblast Growth ◽  
Blocking Antibodies

Mutations that exaggerate signalling of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) give rise to achondroplasia, the most common form of dwarfism in humans. Here we review the clinical features, genetic aspects and molecular pathogenesis of achondroplasia and examine several therapeutic strategies designed to target the mutant receptor or its signalling pathways, including the use of kinase inhibitors, blocking antibodies, physiologic antagonists, RNAi and chaperone inhibitors. We conclude by discussing the challenges of treating growth plate disorders in children.

scholarly journals Fibroblast Growth Factor Receptor 3 Associates with and Tyrosine Phosphorylates p90 RSK2, Leading to RSK2 Activation That Mediates Hematopoietic Transformation

2009 ◽  
Vol 29 (8) ◽  
pp. 2105-2117 ◽  
Author(s):  
Sumin Kang ◽  
Shannon Elf ◽  
Shaozhong Dong ◽  
Taro Hitosugi ◽  
Katherine Lythgoe ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Critical Role ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Marrow Transplant ◽  
Fibroblast Growth ◽  
Murine Bone Marrow

ABSTRACT Dysregulation of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) plays a pathogenic role in a number of human hematopoietic malignancies and solid tumors. These include t(4;14) multiple myeloma associated with ectopic expression of FGFR3 and t(4;12)(p16;p13) acute myeloid leukemia associated with expression of a constitutively activated fusion tyrosine kinase, TEL-FGFR3. We recently reported that FGFR3 directly tyrosine phosphorylates RSK2 at Y529, which consequently regulates RSK2 activation. Here we identified Y707 as an additional tyrosine in RSK2 that is phosphorylated by FGFR3. Phosphorylation at Y707 contributes to RSK2 activation, through a putative disruption of the autoinhibitory αL-helix on the C terminus of RSK2, unlike Y529 phosphorylation, which facilitates ERK binding. Moreover, we found that FGFR3 interacts with RSK2 through residue W332 in the linker region of RSK2 and that this association is required for FGFR3-dependent phosphorylation of RSK2 at Y529 and Y707, as well as the subsequent RSK2 activation. Furthermore, in a murine bone marrow transplant assay, genetic deficiency in RSK2 resulted in a significantly delayed and attenuated myeloproliferative syndrome induced by TEL-FGFR3 as compared with wild-type cells, suggesting a critical role of RSK2 in FGFR3-induced hematopoietic transformation. Our current and previous findings represent a paradigm for tyrosine phosphorylation-dependent regulation of serine-threonine kinases.

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