The structural biology of growth factor receptor activation.
ABSTRACT Stimulation of cells by growth factors triggers cascades of signalling that result in cellular responses such as growth, differentiation, migration and survival. Many growth factors signal through receptor tyrosine kinases, leading to dimerization, trans-phosphorylation and activation of tyrosine kinases that phosphorylate components further downstream of the signal transduction cascade. Using insulin-like growth factor, nerve growth factor, hepatocyte growth factor and fibroblast growth factor as examples, we show that the globular architecture of the growth factors is essential for receptor binding. We describe how nerve growth factor (NGF) is a symmetrical dimer that binds four storage proteins (two alpha-NGF and two gamma-NGF) to give a symmetrical hetero-hexameric 7SNGF organised around the beta-NGF dimer. It binds the extracellular domains of two receptor molecules in a similar way, so dimerising the receptor. Hepatocyte growth factor/scatter factor (HGF/SF) probably binds its receptor as a dimer stabilised by interactions with heparan sulfate, and fibroblast growth factor (FGF) binds its receptor as a dimer cross-linked by heparan sulfate. Surprisingly, insulin and insulin-like growth factor (IGF) bind in the monomeric form to receptors that are already covalent dimers. We propose that, in general, weak binary interactions between growth factor and individual domains of receptors are enhanced by cooperative interactions with further receptor domains, and sometimes other components like heparan, to give rise to specific multi-protein/domain complexes.
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ABSTRACT: PURPOSE: Cataract surgery is blighted by posterior capsule opacification (PCO). Our aim was to understand the biological basis for age-related differences in PCO/wound healing rates. METHODS: Human capsular bags were prepared by sham cataract surgery on donor lenses. FGF and HGF levels were determined using ELISA. Protein synthesis rates were elucidated by 35S-methionine incorporation. U0126, SB203580 and SP600125 were used to disrupt ERK, p38 and JNK mediated signaling respectively. Level of total and phospho ERK, c-jun, P38 and JNK plus cytokines were detected using a BIOPLEX array system. RESULTS: Following a 2-day culture period, significant decreases in IL-1β and IL-6 and increases in IL-10, IL-12, IL-13 and VEGF in the >60 years group were observed compared to < 40 years group. Capsular bags from aged donors contained ≥ levels of HGF and FGF than younger counterparts and had greater rates of protein synthesis. Inhibition of ERK, p38 and JNK signaling significantly suppressed cell coverage on the posterior capsule. pERK, p-c-jun, pP38 and pJNK were consistently lower in aged cell populations; total signaling protein expression was unaffected by age. Serum stimulation increased pERK, p-c-jun, and pJNK levels in cells of all ages and p38 in the aged group only. CONCLUSIONS: Ligand availability to cells is not a limiting factor as we age, but the ability to convert this resource into signaling activity is. We therefore propose that overall signaling efficiency is reduced as a function of age, which consequently limits wound-healing response rates after injury.Investigative ophthalmology & visual science 12/2012; · 3.43 Impact Factor
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ABSTRACT: Heparan sulphates play key roles in conception and early pregnancy events. The role of heparin, a structural analogue, and its application to assisted conception, is largely unknown. Relevant studies were identified by searching PubMed 1966-November 2007 and Google Scholar without limitations. Sensitive search strategies were combined with relevant medical subject headings and text words. The similarities of heparin and heparan, the haemostatic changes induced by ovarian stimulation and the risk of thrombosis, the contribution of thrombophilia to pregnancy and infertility outcomes, early embryo-maternal dialogue and how these various aspects of assisted conception may be modified by heparin are reviewed. Heparin can alter the haemostatic response to controlled ovarian stimulation and modify the risk of thrombosis. It can also modulate many of the fundamental physiological processes required for blastocyst apposition, adherence and implantation and as well as trophoblast differentiation and invasion due to its similarities with heparan sulphates and has the potential to improve pregnancy rates and outcomes.Human Reproduction Update 09/2008; 14(6):623-45. · 9.23 Impact Factor
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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 cross-talk with all other cell types comprising the tumor micro-environment. 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 myo-epithelial cells of CXPA, indicating a paracrine role for benign myoepithelial cell-derived FGF-2. Abnormal paracrine myo-epithelial/epithelial cell interactions and also myoepithelial/ stromal cell interactions could favor tumor growth, invasion and metastasis.Oncology Reports 07/2010; 24(1):155-60. · 2.30 Impact Factor