The structural biology of growth factor receptor activation

Harmer, Nicholas J.; Chirgadze, D.Y.; Kim, Kyung Hyun; Pellegrini, Luca; Blundell, Tom L.

doi:10.1016/s0301-4622(02)00305-8

Cited by 20 publications

(10 citation statements)

References 38 publications

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“…HS has been reported to regulate receptor signaling through the modulation of binding between growth factors (FGF, HGF, and IGF) and their receptors (FGFR and Met) or growth factor binding proteins. [30][31][32][36][37][38][39] Thus, we examined the effect of PAPSS2 depletion on receptor signaling pathways such as FGFR1, Met, and beta subunit of IGF-1 receptor (IGF1Rβ). In PAPSS2-depleted MCF7 cells, we observed augmented FGFR phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Heparan sulfation is essential for the prevention of cellular senescence

et al. 2015

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Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.

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Section: Resultsmentioning

confidence: 99%

Heparan sulfation is essential for the prevention of cellular senescence

et al. 2015

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“…Therefore, a number of recent studies focused on the structural principles governing the domain architecture and their assembly. [98][99][100][101][102][103][104][105][106][107] The emerging concepts, along with the bioinformatics tools that attempt to detect domains and their motions from sequence information alone, 108 may one day lead to a precise de novo engineering of interdomain flexibility, thereby helping achieve the desired functioning of synthetic chimeras. In the mean time, the successful use of feedback techniques such as CD, FRET, and SAXS suggests that gene fusion applications should be accompanied by geometric analysis for appropriate biophysical validation of the linker design process.…”

Section: Design Of Chimeric Proteins With Engineered Domains and Linkersmentioning

confidence: 99%

Control of protein functional dynamics by peptide linkers

2005

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Control of structural flexibility is essential for the proper functioning of a large number of proteins and multiprotein complexes. At the residue level, such flexibility occurs due to local relaxation of peptide bond angles whose cumulative effect may result in large changes in the secondary, tertiary or quaternary structures of protein molecules. Such flexibility, and its absence, most often depends on the nature of interdomain linkages formed by oligopeptides. Both flexible and relatively rigid peptide linkers are found in many multidomain proteins. Linkers are thought to control favorable and unfavorable interactions between adjacent domains by means of variable softness furnished by their primary sequence. Large-scale structural heterogeneity of multidomain proteins and their complexes, facilitated by soft peptide linkers, is now seen as the norm rather than the exception. Biophysical discoveries as well as computational algorithms and databases have reshaped our understanding of the often spectacular biomolecular dynamics enabled by soft linkers. Absence of such motion, as in so-called molecular rulers, also has desirable functional effects in protein architecture. We review here the historic discovery and current understanding of the nature of domains and their linkers from a structural, computational, and biophysical point of view. A number of emerging applications, based on the current understanding of the structural properties

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“…The others, collectively referred to as high molecular weight (HMW) FGF-2, are found predominantly in the nucleus, targeted to this cellular compartment by a nuclear localization sequencelike signal (12)(13)(14). The 18 kDa FGF-2 acts via four FGF specific tyrosine kinase receptors (FGFR1-FGFR4), in concert with soluble or cell surface-bound heparin and heparanproteoglycans, to promote activation of the subsequent intracellular signaling cascade and induction of the biological responses (12,15,16). In contrast, HMW FGF-2 acts in a receptor-independent manner, directly regulating gene expression (13,14).…”

Section: Introductionmentioning

confidence: 99%

FGF-2 is overexpressed in myoepithelial cells of carcinoma ex-pleomorphic adenoma in situ structures

Martinez

Demasi²,

Miguita³

et al. 2010

Oncol Rep

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Abstract. Increasing emphasis has been placed on the role of myoepithelial cells, the contractile components of secretory glands, in the in situ to invasive carcinoma transition. These cells are placed at the interface between luminal epithelial cells and the stromal compartment, which favors their crosstalk with all other cell types comprising the tumor microenvironment. To obtain some clues about this cross-talk and also to better understand our previous immunoprofile study of myoepithelial cells in salivary gland carcinoma ex-pleomorphic adenoma (CXPA), we investigated FGF-2 expression in CXPA in situ structures as well as in cells cultured under conditions attempting to simulate the cellular interactions of this tumor stage. We have observed by immunohistochemistry that myoepithelial cells of CXPA in situ structures overexpress FGF-2. In addition, our results supported by qPCR and Western blotting, demonstrated that the expression of FGF-2 in the benign myoepithelial cells was in fact increased by stimulation with the conditioned medium from malignant cells. Low molecular weight FGF-2, known to be primarily released from the cells to exert its biological activity through receptors, was the predominant FGF-2 form detected in the benign myoepithelial cells. Specific FGF-2 receptors were found in the malignant epithelial but not in the benign myoepithelial cells of CXPA, indicating a paracrine role for benign myoepithelial cell-derived FGF-2. Abnormal paracrine myoepithelial/epithelial cell interactions and also myoepithelial/ stromal cell interactions could favor tumor growth, invasion and metastasis.

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The structural biology of growth factor receptor activation

Cited by 20 publications

References 38 publications

Heparan sulfation is essential for the prevention of cellular senescence

Heparan sulfation is essential for the prevention of cellular senescence

Control of protein functional dynamics by peptide linkers

FGF-2 is overexpressed in myoepithelial cells of carcinoma ex-pleomorphic adenoma in situ structures

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