Biomedical subjects

I Lax

Publications and source records attributed to I Lax.

At least 19 recordsLinked to original sources

PubMed2006

Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis.

Craniosynostosis, the fusion of one or more of the sutures of the skull vault before the brain completes its growth, is a common (1 in 2,500 births) craniofacial abnormality, approximately 20% of which occurrences are caused by gain-of-function mutations in FGF receptors (FGFRs). We describe a genetic and pharmacological approach for the treatment of a murine model system of Crouzon-like craniosynostosis induced by a dominant mutation in Fgfr2c. Using genetically modified mice, we demonstrate that premature fusion of sutures mediated by Crouzon-like activated Fgfr2c mutant is prevented by attenuation of signaling pathways by selective uncoupling between the docking protein Frs2alpha and activated Fgfr2c, resulting in normal skull development. We also demonstrate that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevents premature fusion of sutures without adversely affecting calvaria development. These experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment.

Animals↗

PubMed2005

Essential role of Shp2-binding sites on FRS2alpha for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells.

Mammalian corticogenesis occurs through a complex process that includes neurogenesis, in which neural progenitor cells proliferate, differentiate, and migrate. It has been reported recently that neurogenesis occurs in the subventricular zone (SVZ), a region previously thought to be the primary site of gliogenesis. It has been recognized that in the SVZ, intermediate progenitor cells, derived from radial glial cells that are multipotent neural stem cells, produce only neurons. However, the molecular mechanisms underlying the regulation of neural stem cells and intermediate progenitor cells as well as their contribution to overall corticogenesis remain unknown. The docking protein FRS2alpha is a major mediator of signaling by means of FGFs and neurotrophins. FRS2alpha mediates many of its pleiotropic cellular responses by recruiting the adaptor protein Grb2 and the protein tyrosine phosphatase Shp2 upon ligand stimulation. Here, we report that targeted disruption of Shp2-binding sites in FRS2alpha leads to severe impairment in cerebral cortex development in mutant mice. The defect in corticogenesis appears to be due at least in part to abnormalities in intermediate progenitor cells. Genetic evidence is provided that FRS2alpha plays critical roles in the maintenance of intermediate progenitor cells and in neurogenesis in the cerebral cortex. Moreover, FGF2-responsive neurospheres, which are cell aggregates derived from neural stem/progenitor cells (NSPCs), from FRS2alpha mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2alpha play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.

Animals↗

PubMed2005

Cellular signaling by fibroblast growth factor receptors.

The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. A variety of human skeletal dysplasias have been linked to specific point mutations in FGFR1, FGFR2 and FGFR3 leading to severe impairment in cranial, digital and skeletal development. Gain of function mutations in FGFRs were also identified in a variety of human cancers such as myeloproliferative syndromes, lymphomas, prostate and breast cancers as well as other malignant diseases. The binding of FGF and HSPG to the extracellular ligand domain of FGFR induces receptor dimerization, activation and autophosphorylation of multiple tyrosine residues in the cytoplasmic domain of the receptor molecule. A variety of signaling proteins are phosphorylated in response to FGF stimulation including Shc, phospholipase-Cgamma, STAT1, Gab1 and FRS2alpha leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. The docking proteins FRS2alpha and FRS2beta are major mediators of the Ras/MAPK and PI-3 kinase/Akt signaling pathways as well as negative feedback mechanisms that fine-tune the signal that is initiated at the cell surface following FGFR stimulation.

Fibroblast Growth Factors↗

PubMed2005

The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development.

The docking protein FRS2alpha is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2alpha in vivo remains unknown. In this report, we show that Frs2alpha-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 FRS2alpha 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 FRS2alpha 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 Frs2alpha-null embryos. These experiments underscore the critical role of FRS2alpha in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.

Animals↗

PubMed2004

Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina.

Early development of the lens and retina depends upon reciprocal inductive interactions between the embryonic surface ectoderm and the underlying neuroepithelium of the optic vesicle. FGF signaling has been implicated in this signal exchange. The docking protein FRS2alpha is a major mediator of FGF signaling by providing a link between FGF receptors (FGFRs) and a variety of intracellular signaling pathways. After FGF stimulation, tyrosine-phosphorylated FRS2alpha recruits four molecules of the adaptor protein Grb2 and two molecules of the protein tyrosine phosphatase Shp2, resulting in activation of the Ras/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase/Akt signaling pathways. In this report, we explore the role of signaling pathways downstream of FRS2alpha in eye development by analyzing the phenotypes of mice that carry point mutations in either the Grb2-(Frs2alpha(4F)) or the Shp2-binding sites (Frs2alpha(2F)) of FRS2alpha. Although Frs2alpha(4F/4F) mice exhibited normal early eye development, all Frs2alpha(2F/2F) embryos were defective in eye development and showed anophthalmia or microphthalmia. Consistent with the critical role of FRS2alpha in FGF signaling, the level of activated extracellular signal-regulated kinase in Frs2alpha(2F/2F) embryos was significantly lower than that observed in wild-type embryos. Furthermore, expression of Pax6 and Six3, molecular markers for lens induction, were decreased in the Frs2alpha(2F/2F) presumptive lens ectoderm. Similarly, the expression of Chx10 and Bmp4, genes required for retinal precursor proliferation and for lens development, respectively, was also decreased in the optic vesicles of Frs2alpha(2F/2F) mice. These experiments demonstrate that intracellular signals that depend on specific tyrosine residues in FRS2alpha lie upstream of gene products critical for induction of lens and retina.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways.

The docking protein FRS2 alpha has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs). We have demonstrated that targeted disruption of FRS2 alpha gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0--E7.5. Experiments with FRS2 alpha-deficient fibroblasts demonstrate that FRS2 alpha plays a critical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation, phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, and cell proliferation. Following FGF stimulation, tyrosine phosphorylated FRS2 alpha functions as a site for coordinated assembly of a multiprotein complex that includes Gab1 and the effector proteins that are recruited by this docking protein. Furthermore, we demonstrate that different tyrosine phosphorylation sites on FRS2 alpha are responsible for mediating different FGF-induced biological responses. These experiments establish the central role of FRS2 alpha in signaling via FGFRs and demonstrate that FRS2 alpha mediates multiple FGFR-dependent signaling pathways critical for embryonic development.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins.

The docking protein FRS2 is a major downstream effector that links fibroblast growth factor (FGF) and nerve growth factor receptors with the Ras/mitogen-activated protein kinase signaling cascade. In this report, we demonstrate that FRS2 also plays a pivotal role in FGF-induced recruitment and activation of phosphatidylinositol 3-kinase (PI3-kinase). We demonstrate that tyrosine phosphorylation of FRS2alpha leads to Grb2-mediated complex formation with the docking protein Gab1 and its tyrosine phosphorylation, resulting in the recruitment and activation of PI3-kinase. Furthermore, Grb2 bound to tyrosine-phosphorylated FRS2 through its SH2 domain interacts primarily via its carboxyl-terminal SH3 domain with a proline-rich region in Gab1 and via its amino-terminal SH3 domain with the nucleotide exchange factor Sos1. Assembly of FRS2alpha:Grb2:Gab1 complex induced by FGF stimulation results in activation of PI3-kinase and downstream effector proteins such as the S/T kinase Akt, whose cellular localization and activity are regulated by products of PI3-kinase. These experiments reveal a unique mechanism for generation of signal diversity by growth factor-induced coordinated assembly of a multidocking protein complex that can activate the Ras/mitogen-activated protein kinase cascade to induce cell proliferation and differentiation, and PI3-kinase to activate a mediator of a cell survival pathway.

3T3 Cells↗

PubMed2001

Risk for hemorrhage during the 2-year latency period following gamma knife radiosurgery for arteriovenous malformations.

PURPOSE: Radiosurgery does not immediately obliterate an arteriovenous malformation (AVM), and the risk for hemorrhage still persists until the AVM is occluded. There is controversy about whether this risk is altered after as compared to before radiosurgery. The aim of this paper is to study this topic further and to suggest a model to predict the risk for posttreatment hemorrhage. METHODS AND MATERIALS: The incidence of hemorrhages within the first 24 months following Gamma Knife radiosurgery was studied retrospectively among 1593 AVM patients, and was related to patient, AVM, and treatment parameters. RESULTS: Fifty-six patients experienced a hemorrhage in the latency period, representing an average annual incidence of 1.8%. The incidence of posttreatment hemorrhage was related to the patient's age, AVM volume, minimum dose, and average dose delivered to the AVM nidus. Based on these observations, an equation was defined that could quantify the probability for a posttreatment hemorrhage to occur. CONCLUSION: A model that can predict the probability for a hemorrhage within the first 24 months after radiosurgery is presented. The risk is higher for larger AVMs and for older patients, and it is lower when higher doses of radiation are used.

Adult↗

PubMed2001

Gamma knife outcome models as a reference standard in the embolisation of cerebral arteriovenous malformations.

BACKGROUND: We sought to utilise outcome models from Gamma Knife radiosurgery (GKRS) to cerebral arteriovenous malformations (AVM) as a reference standard in assessing the clinical outcome of embolisation, thus comparing the outcomes of two different management alternatives, in the same patients. METHODS: 87 consecutive patients with 88 AVM were admitted during 1997-1999 for initial embolisation of an AVM. The clinical outcomes were recorded prospectively. Angiography under stereotactic conditions with measurement of AVM volume was performed before and after embolisation. GKRS outcome models were used to predict obliteration rate, complication rate and risk of haemorrhage before and after embolisation. The clinical outcome of embolisation followed by predicted outcome of adjunct GKRS was then compared with the predicted outcome of GKRS as the only treatment. FINDINGS: Eight patients were subjected to microcatheterisation but not to embolisation. By the end of the study period, embolisation had been terminated in 55 patients out of 80 (69%). The predicted outcome of GKRS alone was 58 obliterations and 12 complications while that of the combined management was 58 obliterations and 15 complications. The difference was not significant on the p < 0.1 level. INTERPRETATION: Volume measurement from angiography and outcome models from Gamma Knife radiosurgery are useful as a reference standard in the management of AVM. Absolute volume reduction from embolisation is most prominent for AVM > 10 ml and thus facilitates subsequent radiosurgery. For AVM < or = 10 ml, GKRS as the only treatment can be an alternative to primary embolisation, particularly if no significant volume reduction or obviously beneficial effect of targeted embolisation is expected. Further prospective studies are needed to identify subgroups in which one treatment has advantages over the other.

Adolescent↗

PubMed2001

Partial irradiation of the heart.

Radiation-induced heart disease (RIHD) includes pericarditis, ischemic heart disease, and myocardial infarction and leads in some cases to fatal complications. It has been shown that the increased survival due to radiotherapy could be negated by excess deaths from RIHD in breast cancer radiotherapy for left-sided tumors. Subclinical effects following irradiation have been detected in several studies both of breast cancer and Hodgkin's irradiation. The dose-volume response relationships describing cardiac complications have been studied for pericarditis and cardiac mortality by means of biologic models, including the well-known Lyman-Kutcher-Burman (LKB) model and Källman's relative seriality model. Studies by Martel and coworkers on pericarditis and by Gagliardi and coworkers on cardiac mortality are reviewed. The anatomical and functional definition of the heart represents a key issue in modeling, as it affects strongly the dosimetrical data to be used as input data in the models. Several treatment strategies to decrease heart irradiation, based on models and/or based on dose-distribution evaluations, are reviewed. It is concluded that left-sided breast cancer patients should always be 3-dimensional (3D) dose planned.

Breast Neoplasms↗

PubMed2001

Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.

The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for "glial cell-derived neurotrophic factors") family of ligands. Mutations in the RET gene were implicated in Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by binding of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET that also functions as a binding site for Shc. However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins. We demonstrate that oncogenic RET-PTC proteins are associated with FRS2 constitutively, leading to tyrosine phosphorylation of FRS2, MAP kinase stimulation, and cell proliferation. However, loss-of-function HSCR-associated RET mutants exhibit impaired FRS2 binding and reduced MAP kinase activation. These experiments demonstrate that FRS2 couples both ligand-regulated and oncogenic forms of RET, with the MAP kinase signaling cascade as part of the response of RET under normal biological conditions and pathological conditions, such as MEN 2 and papillary thyroid carcinomas.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Radiation pneumonitis after breast cancer irradiation: analysis of the complication probability using the relative seriality model.

BACKGROUND: Toxicity of the respiratory system is quite common after radiotherapy of thoracic tumors; breast cancer patients represent one of the groups for which there is also a long expected survival. The quantification of lung tissue response to irradiation is important in designing treatments associated with a minimum of complications and maximum tumor control. METHODS: The study population consisted of 68 patients who received irradiation for breast cancer at Stage II. Radiation pneumonitis was retrospectively assessed on the basis of clinical symptoms and radiological findings. For each patient, a measure of the exposure (i.e., the lung dose-volume histogram [DVH]) and a measure of the outcome was available. Based on these data, a maximum likelihood fitting to the relative seriality model was performed. The uncertainties of the model parameters were calculated and their impact on the dose-response curve was studied. The optimum parameter set was then applied to 5 other patient groups treated for breast cancer, and the normal tissue complication probability (NTCP) was calculated. Each group was individuated by the radiotherapy treatment technique used; the dose distribution in the lung was described by a mean DVH and the incidence of radiation pneumonitis in each group was known. Lung radiosensitivity was assumed to be homogeneous through all of the calculations. RESULTS: The relative seriality model could describe the dataset. The volume effect was found to be relevant in the description of radiation pneumonitis. Age was found to be associated with increased risk of radiation pneumonitis. Two distinct dose-response curves were obtained by splitting the group according to age. The impact of the parameter uncertainties on the dose-response curve was quite large. The parameter set determined could be used predictively on 3 of the 5 patient groups. CONCLUSION: The complication data could be modeled with the relative seriality model. However, further independent datasets, classified according to the same endpoint, must be analyzed before introducing NTCP modeling in clinical practice.

Age Factors↗

PubMed2000

Long-term cardiac mortality following radiation therapy for Hodgkin's disease: analysis with the relative seriality model.

PURPOSE: (a) To assess the increased risk of death due to ischemic heart disease (IHD) in a group of patients treated for Hodgkin's disease (HD) with radiation therapy (RT) as the primary treatment. (b) To quantify the dose response of IHD using a biophysical model. MATERIALS AND METHODS: Patient material consisted of 157 patients diagnosed for HD between 1972 and 1985 who received RT as the primary treatment at Radiumhemmet, Karolinska Hospital. The general population formed the control group. The RT treatments were reconstructed based on the individual treatment data and simulator films. Individual clinical and dosimetrical data were analyzed with the relative seriality model. The material was also analyzed grouping the material according to dose-volume constraints. RESULTS: Of the 157 patients, 13 (8.3%) died due to IHD. The standardized mortality ratio (SMR) was 5.0 (95% CI, 2.7-8.6). Analysis of dose-volume histograms (DVH) showed an increasing risk with increasing dose to a larger volume fraction. The observed individual clinical complication data could not be modeled unambiguously. The group analysis resulted in the dose-response parameters: D(50)=71 Gy, gamma=0.96 and s=1.0. CONCLUSIONS: A significantly increased risk of death due to IHD following RT for HD was found. The risk was found to increase with higher dose and larger volume fraction irradiated.

Adolescent↗

PubMed2000

FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors.

The docking protein FRS2 was implicated in the transmission of extracellular signals from the fibroblast growth factor (FGF) or nerve growth factor (NGF) receptors to the Ras/mitogen-activated protein kinase signaling cascade. The two members of the FRS2 family, FRS2alpha and FRS2beta, are structurally very similar. Each is composed of an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, and a C-terminal tail containing multiple binding sites for the SH2 domains of the adapter protein Grb2 and the protein tyrosine phosphatase Shp2. Here we show that the PTB domains of both the alpha and beta isoforms of FRS2 bind directly to the FGF or NGF receptors. The PTB domains of the FRS2 proteins bind to a highly conserved sequence in the juxtamembrane region of FGFR1. While FGFR1 interacts with FRS2 constitutively, independent of ligand stimulation and tyrosine phosphorylation, NGF receptor (TrkA) binding to FRS2 is strongly dependent on receptor activation. Complex formation with TrkA is dependent on phosphorylation of Y490, a canonical PTB domain binding site that also functions as a binding site for Shc (NPXpY). Using deletion and alanine scanning mutagenesis as well as peptide competition assays, we demonstrate that the PTB domains of the FRS2 proteins specifically recognize two different primary structures in two different receptors in a phosphorylation-dependent or -independent manner. In addition, NGF-induced tyrosine phosphorylation of FRS2alpha is diminished in cells that overexpress a kinase-inactive mutant of FGFR1. This experiment suggests that FGFR1 may regulate signaling via NGF receptors by sequestering a common key element which both receptors utilize for transmitting their signals. The multiple interactions mediated by FRS2 appear to play an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Stoichiometry, kinetic and binding analysis of the interaction between epidermal growth factor (EGF) and the extracellular domain of the EGF receptor.

The kinetics, binding equilibria and stoichiometry of the interaction between epidermal growth factor and the soluble extracellular domain of the epidermal growth factor receptor (sEGFR), produced in CHO cells using a bioreactor, have been studied by three methods: analytical ultracentrifugation, biosensor analysis using surface plasmon resonance detection (BIAcore 2000) and fluorescence anisotropy. These studies were performed with an sEGFR preparation purified in the absence of detergent using a mild two step chromatographic procedure employing anion exchange and size exclusion HPLC. The fluorescence anisotropy and analytical ultracentrifugation data indicated a 1:1 molar binding ratio between EGF and the sEGFR. Analytical ultracentrifugation further indicated that the complex comprised 2EGF:2sEGFR, consistent with the model proposed recently by Lemmon et al. (1997). Global analysis of the BIAcore binding data showed that a simple Langmuirian interaction does not adequately describe the EGF:sEGFR interaction and that more complex interaction mechanisms are operative. Furthermore, analysis of solution binding data using either fluorescence anisotropy or the biosensor, to determine directly the concentration of free sEGFR in solution competition experiments, yielded Scatchard plots which were biphasic and Hill coefficients of less than unity. Taken together our data indicate that in solution there are two sEGFR populations; one which binds EGF with a KD of 2-20 nM and the other with a KD of 400-550 nM.

Amino Acid Sequence↗

PubMed1999

Can the probability for obliteration after radiosurgery for arteriovenous malformations be accurately predicted?

PURPOSE: To investigate how accurate different models predict the probability for obliteration following radiosurgery for an arteriovenous malformation (AVM). METHODS AND MATERIALS: The probability for obliteration was calculated for all 838 AVMs with a known treatment outcome and treated at the Karolinska Hospital with Gamma Knife surgery 1970-1993. Four different models were used for the calculation, resulting in four different values of the probability for obliteration. The calculated prediction values were added for each model, and the total number of predicted obliteration compared to that observed in the whole patient material as well as in different subgroups. RESULTS: Three of the four models predicted the total number of obliterations accurately. In two of those three models, the accuracy of the prediction was dependent on AVM volume and treatment dose. In one model only, the prediction was accurate and independent of all investigated parameters. CONCLUSIONS: The probability for obliteration was accurately predicted by one of the models analyzed. In this model, the probability for obliteration was related to the dose to the AVM periphery only. The AVM volume had no independent impact on the probability for obliteration. There was a trend that AVMs with a central location had a better obliteration rate than predicted.

Adult↗

PubMed1998

Nerve growth factor acutely reduces chemical transmission by means of postsynaptic TrkA-like receptors in squid giant synapse.

Tyrosine phosphorylation has been shown to be an important modulator of synaptic transmission in both vertebrates and invertebrates. Such findings hint toward the existence of extracellular ligands capable of activating this widely represented signaling mechanism at or close to the synapse. Examples of such ligands are the peptide growth factors which, on binding, activate receptor tyrosine kinases. To gain insight into the physiological consequences of receptor tyrosine kinase activation in squid giant synapse, a series of growth factors was tested in this preparation. Electrophysiological, pharmacological, and biochemical analysis demonstrated that nerve growth factor (NGF) triggers an acute and specific reduction of the postsynaptic potential amplitude, without affecting the presynaptic spike generation or presynaptic calcium current. The NGF target is localized at a postsynaptic site and involves a new TrkA-like receptor. The squid receptor crossreacts with antibodies generated against mammalian TrkA, is tyrosine phosphorylated in response to NGF stimulation, and is blocked by specific pharmacological inhibitors. The modulation described emphasizes the important role of growth factors on invertebrate synaptic transmission.

Animals↗

PubMed1998

Structure of a heparin-linked biologically active dimer of fibroblast growth factor.

The fibroblast growth factors (FGFs) form a large family of structurally related, multifunctional proteins that regulate various biological responses. They mediate cellular functions by binding to transmembrane FGF receptors, which are protein tyrosine kinases. FGF receptors are activated by oligomerization, and both this activation and FGF-stimulated biological responses require heparin-like molecules as well as FGF. Heparins are linear anionic polysaccharide chains; they are typically heterogeneously sulphated on alternating L-iduronic and D-glucosamino sugars, and are nearly ubiquitous in animal tissues as heparan sulphate proteoglycans on cell surfaces and in the extracellular matrix. Although several crystal structures have been described for FGF molecules in complexes with heparin-like sugars, the nature of a biologically active complex has been unknown until now. Here we describe the X-ray crystal structure, at 2.9 A resolution, of a biologically active dimer of human acidic FGF in a complex with a fully sulphated, homogeneous heparin decassacharide. The dimerization of heparin-linked acidic FGF observed here is an elegant mechanism for the modulation of signalling through combinatorial homodimerization and heterodimerization of the 12 known members of the FGF family.

Animals↗