Fibroblast Growth Factor Receptor Like-1 (FGFRL1) Interacts with SHP-1 Phosphatase at Insulin Secretory Granules and Induces Beta-cell ERK1/2 Protein Activation

Silva, Pamuditha N.; Altamentova, Svetlana M.; Kilkenny, Dawn M.; Rocheleau, Jonathan V.

doi:10.1074/jbc.m112.440677

Cited by 44 publications

(47 citation statements)

References 43 publications

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“…HEAT-on-a-chip will also improve biochemical assays that require high transduction efficiency. For example, we previously showed fibroblast growth factor receptor-like 1 (FGFRL1) over-expression increases insulin production and insulin secretion in a murine beta-cell line 54 . We now plan to extend our findings to intact primary human islets to perform higher sensitivity insulin ELISA or conduct western immunoblot analysis on critical signalling pathways, given that both of these biochemical assays require high transduction efficiency to discern significant biological effects.…”

Section: Discussionmentioning

confidence: 99%

Highly efficient adenoviral transduction of pancreatic islets using a microfluidic device

et al. 2016

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Tissues are challenging to genetically manipulate due to limited penetration of viral particles resulting in low transduction efficiency. We are particularly interested in expressing genetically-encoded sensors in ex vivo pancreatic islets to measure glucose-stimulated metabolism, however poor viral penetration biases these measurements to only a subset of cells at the periphery. To increase mass transfer of viral particles, we designed a microfluidic device that holds islets in parallel hydrodynamic traps connected by an expanding by-pass channel. We modeled viral particle flow into the tissue using fluorescently-labelled gold nanoparticles of varying sizes and showed a penetration threshold of only ∼5 nm. To increase this threshold, we used EDTA to transiently reduce cell-cell adhesion and expand intercellular space. Ultimately, a combination of media flow and ETDA treatment significantly increased adenoviral transduction to the core of the islet. As proof-of-principle, we used this protocol to transduce an ER-targeted redox sensitive sensor (eroGFP), and revealed significantly greater ER redox capacity at core islet cells. Overall, these data demonstrate a robust method to enhance transduction efficiency of islets, and potentially other tissues, by using a combination of microfluidic flow and transient tissue expansion.

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Section: Discussionmentioning

confidence: 99%

Highly efficient adenoviral transduction of pancreatic islets using a microfluidic device

et al. 2016

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“…Fgfrl1 was presumed to inhibit FGF signaling by sequestering ligand (Steinberg et al, 2010). However, new evidence suggests that Fgfrl1 facilitates FGF liganddependent MAPK activation (Silva et al, 2013). Further, Fgfrl1 also enhanced FGF-stimulated Erk1/2 activation, implicating a role in ligand-dependent signaling (Silva et al, 2013).…”

Section: Prox1 Regulates the Expression Of Fgfr3 Lctl And Fgfrl1mentioning

confidence: 99%

“…However, new evidence suggests that Fgfrl1 facilitates FGF liganddependent MAPK activation (Silva et al, 2013). Further, Fgfrl1 also enhanced FGF-stimulated Erk1/2 activation, implicating a role in ligand-dependent signaling (Silva et al, 2013). Intriguingly, Fgfrl1 also increases basal Erk1/2 phosphorylation independently of FGF ligand.…”

Section: Prox1 Regulates the Expression Of Fgfr3 Lctl And Fgfrl1mentioning

confidence: 99%

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

Audette

Anand

et al. 2015

Development

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Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF.

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“…The FGFR family is generally composed of three extracellular ig-like domains, a transmembrane helical region and an intracellular tyrosine kinase domain. [8][9][10] Gerber et al 9 demonstrated that FGFRL1 may be a positive regulator of the FGF signalling pathway rather than a decoy receptor during renal development. 5 Therefore, FGFRL1 is widely considered to negatively regulate the FGF signalling pathway by combining extracellular ligand to prevent its interaction with typical receptors.…”

Section: Introductionmentioning

confidence: 99%

“…However, FGFRL1 lacks the classic tyrosine kinase regions and contains a peculiar histone-rich region instead. 10 Recently, increasing evidence has shown that FGFRL1 plays a key role in many cancers, and overexpression of FGFRL1 has been associated with proliferation and metastasis of prostate and gastric cancer cells. Several studies have generated data supporting this hypothesis, 6,7 whereas others have found conflicting results.…”

Section: Introductionmentioning

confidence: 99%

FGFRL1 affects chemoresistance of small‐cell lung cancer by modulating the PI3K/Akt pathway via ENO1

Chen

Zheng

et al. 2020

J Cellular Molecular Medi

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Fibroblast growth factor receptor-like 1 (FGFRL1), a member of the FGFR family, has been demonstrated to play important roles in various cancers. However, the role of FGFRL1 in small-cell lung cancer (SCLC) remains unclear. Our study aimed to investigate the role of FGFRL1 in chemoresistance of SCLC and elucidate the possible molecular mechanism. We found that FGFRL1 levels are significantly up-regulated in multidrug-resistant SCLC cells (H69AR and H446DDP) compared with the sensitive parental cells (H69 and H446). In addition, clinical samples showed that FGFRL1 was overexpressed in SCLC tissues, and high FGFRL1 expression was associated with the clinical stage, chemotherapy response and survival time of SCLC patients. Knockdown of FGFRL1 in chemoresistant SCLC cells increased chemosensitivity byincreasing cell apoptosis and cell cycle arrest, whereas overexpression of FGFRL1 in chemosensitive SCLC cells produced the opposite results. Mechanistic investigations showed that FGFRL1 interacts with ENO1, and FGFRL1 was found to regulate the expression of ENO1 and its downstream signalling pathway (the PI3K/Akt pathway) in SCLC cells. In brief, our study demonstrated that FGFRL1 modulates chemoresistance of SCLC by regulating the ENO1-PI3K/Akt pathway. FGFRL1 may be a predictor and a potential therapeutic target for chemoresistance in SCLC. K E Y W O R D Schemoresistance, ENO1, FGFRL1, PI3K/Akt pathway, small-cell lung cancer

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Fibroblast Growth Factor Receptor Like-1 (FGFRL1) Interacts with SHP-1 Phosphatase at Insulin Secretory Granules and Induces Beta-cell ERK1/2 Protein Activation

Cited by 44 publications

References 43 publications

Highly efficient adenoviral transduction of pancreatic islets using a microfluidic device

Highly efficient adenoviral transduction of pancreatic islets using a microfluidic device

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

FGFRL1 affects chemoresistance of small‐cell lung cancer by modulating the PI3K/Akt pathway via ENO1

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