MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma

Masih‐Khan, Esther; Trudel, Suzanne; Heise, Carla; Li, Zhihua; Paterson, Joshua; Nadeem, Vincent; Wei, Ellen; Roodman, David; Claudio, Jaime O.; Bergsagel, P. Leif; Stewart, A. Keith

doi:10.1182/blood-2006-04-017087

Cited by 75 publications

(59 citation statements)

References 41 publications

(66 reference statements)

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“…Besides its role in development of osteolytic bone destruction, MIP-1α might play a pivotal role in the pathogenesis of MM directly affecting cell signaling pathways that mediate growth, survival, and migration in MM cells and promoting adhesive interactions between MM and stromal cells [27]. Consistent with the potential implication of DUSP family in FGF-R3 signaling [36], GEP of RPI-1-treated cells also revealed the upregulation of DUSP10, a negative regulator of the MAP kinase cascade.…”

Section: Discussionsupporting

confidence: 53%

See 1 more Smart Citation

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

Cassinelli¹,

Ronchetti²,

Laccabue³

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Section: Discussionsupporting

confidence: 53%

“…16 [36]. In particular, we observed a concordant modulation at every time point of SAT-1 and SRM, both involved in the cellular polyamine metabolism [37].…”

Section: Discussionmentioning

confidence: 99%

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

Cassinelli¹,

Ronchetti²,

Laccabue³

et al. 2009

Biochemical Pharmacology

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“…In addition, OPM2 and KMS11 harbor highly activating FGFR3 mutations (K650E and Y373C, respectively), common in severe forms of FGFR3-related skeletal dysplasia and cancer (1, 2). In agreement with previous studies, FGFR3 activation in OPM2 and KMS11 cell lead to activation of ERK MAPK and transcriptional induction of CCL3 and CCL4 chemokines (16,17), 3 with both phenotypes being vulnerable to NF449 (Fig. 3).…”

Section: Discussionsupporting

confidence: 79%

NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells

Krejčı́

Murakami

Procházková

et al. 2010

Journal of Biological Chemistry

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The FGFR3 receptor tyrosine kinase represents an attractive target for therapy due to its role in several human disorders, including skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas. By using molecular library screening, we identified a compound named NF449 with inhibitory activity toward FGFR3 signaling. In cultured chondrocytes and murine limb organ culture, NF449 rescued FGFR3-mediated extracellular matrix loss and growth inhibition, which represent two major cellular phenotypes of aberrant FGFR3 signaling in cartilage. Similarly, NF449 antagonized FGFR3 action in the multiple myeloma cell lines OPM2 and KMS11, as evidenced by NF449-mediated reversal of ERK MAPK activation and transcript accumulation of CCL3 and CCL4 chemokines, both of which are induced by FGFR3 activation. In cell-free kinase assays, NF449 inhibited the kinase activity of both wild type and a disease-associated FGFR3 mutant (K650E) in a fashion that appeared non-competitive with ATP. Our data identify NF449 as a novel antagonist of FGFR3 signaling, useful for FGFR3 inhibition alone or in combination with inhibitors that target the ATP binding site.FGFR3 (fibroblast growth factor receptor 3) is a transmembrane tyrosine kinase that serves as a receptor for the members of the fibroblast growth factor (FGF) 2 family and functions in many biological processes, including cell proliferation, differentiation, migration, and survival. To date, activating mutations in FGFR3 have been associated with several human disorders, such as skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas (1-4).Among the skeletal dysplasias, activating FGFR3 mutations cause achondroplasia, the most common form of human skeletal dysplasia, and thanatophoric dysplasia, the most common form of lethal skeletal dysplasia (1). Long bones of individuals suffering from FGFR3-related skeletal dysplasias show markedly shortened zones of chondrocyte proliferation and differentiation, whereas Fgfr3 knock-out mice and humans without functional FGFR3 demonstrate skeletal overgrowth, together implying the role of FGFR3 as a negative regulator of bone growth (5).Apart from cartilage, ϳ15% of patients suffering from multiple myeloma markedly up-regulate FGFR3 as a consequence of a t(4;14)(p16.3;q32) translocation, with a fraction of patients also harboring activating mutations in FGFR3, identical to those found in the skeletal dysplasias (2, 3). Ectopic expression of FGFR3 enhances multiple myeloma cell proliferation and survival, demonstrating the oncogenic potential of FGFR3 (6).Given its role in human disease, FGFR3 signaling represents an attractive target for therapy. There is no treatment available for achondroplasia at present, thus inciting the development of novel approaches to target FGFR3. The aim of this study was to identify novel inhibitors of FGFR3 signaling in cellular environments relevant to FGFR3-related disorders. We recently established a chondrocyte cell-based reporter assay suitable for identification of inhibitors of ...

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“…The 10 M concentration of SU5402 used in these experiments has been shown to effectively block FGF signaling while having no effect on platelet-derived growth factor-induced tyrosine kinase activity (Mohammadi et al, 1997). SU5402 was originally shown to inhibit signaling through FGFR1, but subsequent studies have shown that it also inhibits signaling through other FGF receptors (Maeda et al, 2005;BernardPierrot et al, 2006;Masih-Khan et al, 2006;Urban et al, 2006). Dimethyl sulfoxide (DMSO) controls displayed typical lung explant branching morphogenesis (Fig.…”

Section: Su5402 Blocks Embryonic Lung Branching In Culturementioning

confidence: 99%

Elf5 is an epithelium‐specific, fibroblast growth factor–sensitive transcription factor in the embryonic lung

Metzger¹,

Xu²,

Shannon³

2007

Developmental Dynamics

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Fibroblast growth factor (FGF) signaling has been shown to be essential for many aspects of normal lung development. To determine epithelial targets of FGF signaling, we cultured embryonic day (E) 11.5 mouse lungs for 24 hr in the presence or absence of the FGF receptor antagonist SU5402, which inhibited branching morphogenesis. Affymetrix gene chip analysis of treated and control epithelia identified several genes regulated by FGF signaling, including Elf5, a member of the Epithelial-specific Ets family of transcription factors. SU5402 reduced Elf5 expression in mesenchyme-free cultures of E12.5 epithelium, demonstrating that the inhibition was direct. In situ hybridization revealed that Elf5 had a dynamic pattern of expression during lung development. We found that expression of Elf5 was induced by FGF7 and FGF10, ligands that primarily bind FGFR2b. To further define the pathways by which FGFs activate Elf5 expression, we cultured E11.5 lung tips in the presence of compounds to inhibit FGF receptors (SU5402), PI3-Kinase/Akt-mediated signaling (LY294002), and MAP Kinase/Erk-mediated signaling (U0126). We found that SU5402 and LY294002 significantly reduced Elf5 expression, whereas U0126 had no effect. LY294002 also reduced Elf5 expression in cultures of purified epithelium. Finally, pAkt was coexpressed with Elf5 in the proximal epithelial airways of E17.5 lungs. These results demonstrate that Elf5 is an FGF-sensitive transcription factor in the lung with a dynamic pattern of expression and that FGF regulation of Elf5 by means of FGFR2b occurs through the PI3-Kinase/Akt pathway.

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MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma

Cited by 75 publications

References 41 publications

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells

Elf5 is an epithelium‐specific, fibroblast growth factor–sensitive transcription factor in the embryonic lung

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