藥學專業(yè)畢業(yè)論文外文翻譯--fgf家族生物學，病理生理學和治療學簡述（英文）

1、There are 18 mammalian fibroblast growth factors (FGF1–FGF10 and FGF16–FGF23) which are grouped into 6 subfamilies based on differences in sequence homology and phylogeny: FGF1 and FGF2; FGF3, FGF7, FGF10, FGF22; FGF

2、4, FGF5 and FGF6; FGF8, FGF17 and FGF18; FGF9, FGF16 and FGF20; and FGF19, FGF21 and FGF23 (REF. 1). The numbered ‘FGFs’ that are unassigned to subfamilies — the FGF homologous factors (previously known as FGF11–FGF14)

3、 — have high sequence identity with the FGF family but do not activate FGF receptors (FGFRs) and are therefore not generally considered members of the FGF family2 (BOX 1); FGF15 is the mouse orthologue of human FGF19

4、. FGFs are classi- cally considered to be paracrine factors and are known for their roles in tissue patterning and organogenesis during embryogenesis: the first five subfamilies fall into this category. By contrast, the

5、 FGF19, FGF21 and FGF23 subfamily has recently been shown to function in an endocrine manner, dependent on the presence of klotho proteins in their target tissues, to regulate bile acid, choles- terol, glucose, vitami

6、n D and phosphate homeostasis3–6.The involvement of FGF signalling in human disease is well documented. Deregulated FGF signalling can con- tribute to pathological conditions either through gain- or loss-of-function mut

7、ations in the ligands themselves — for example, FGF23 gain of function in autosomal dominant hypophosphataemic rickets7, FGF10 loss of function in lacrimo-auriculo-dento-digital syndrome (LADD syn- drome)8, FGF3 loss of

8、 function in deafness9 and FGF8 loss of function in Kallmann syndrome10 — or through gain- or loss-of-function mutations in FGFRs, which contribute to many skeletal syndromes41, Kallmann syndrome36, LADD syndrome54 an

9、d cancer. Therapeutic approaches using exogenous FGFs, antibodies or small molecules are still relatively new, and many avenues of investigation remain open. Recombinant FGF7 is already in use for the treatment of ch

10、emoradiation-induced oral mucositis. Future application of the FGFs in renal disease, glucose and phosphate homeostasis, stem cell research, tissue repair and bioengineering, and angiogenesis is expected. Continued ef

11、forts to understand the structural biology of FGF–FGFR interactions will play a key part in driving the discovery of new therapies.In this article, we briefly review current knowledge regarding FGF–FGFR signalling and

12、then focus on the biology, pathology and recent developments regarding the pharmacological applications of each ligand.The FGF–FGFR signalling system FGFs. All FGFs, except those in subfamilies FGF1 and FGF2, and FGF9

13、, FGF16 and FGF20, have signal peptides. The FGF9, FGF16 and FGF20 subfamily is nonetheless secreted through the traditional endoplasmic reticulum (ER)–Golgi secretory pathway11, whereas the FGF1 and FGF2 subfamily

14、is secreted independently12. FGFs have a homologous core region that consists of 120–130 amino acids ordered into 12 antiparallel β-strands (β1–β12) flanked by divergent amino and carboxyl termini (FIG. 1a). In general

15、, primary sequence variation of the N- and C-terminal tails of FGFs accounts for the differ- ent biology of the ligands13 (FIG. 1b). The heparan sulphate glycosaminoglycan (HSGAG) binding site (HBS) within the FGF core

16、 is composed of the β1–β2 loop and parts of the region spanning β10 and β12. For paracrine FGFs, Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA. e-mails: Andrew.Beenken

17、@med.nyu.edu; Moosa.Mohammadi@ nyumc.orgdoi:10.1038/nrd2792Autosomal dominant hypophosphataemic rickets A hereditary disorder of phosphate wasting characterized by rickets, lower extremity deformities and osteomalaci

18、a.Lacrimo-auriculo-dento- digital syndrome (LADD). A syndrome characterized by abnormalities of the digits and teeth, low-set ears and aplasia of the lacrimal and salivary glands. Mutations in FGFR2 and FGF10 are known t

19、o cause LADD.Kallmann syndromeThis syndrome results from a deficiency of gonadotropin-releasing hormone, which leads to hypogonadism. Mutations in FGFR1c and FGF8 are known to cause Kallmann syndrome.The FGF family: biol

20、ogy, pathophysiology and therapyAndrew Beenken and Moosa MohammadiAbstract | The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphog

21、enesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 s

22、ubfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molec

23、ule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.REVIEWSNATuRE REvIEwS | Drug D

24、iscovery voLumE 8 | mARCH 2009 | 235© 2009 Macmillan Publishers Limited. All rights reservedcaNature Reviews | Drug DiscoveryFGF1 FGF2 FGF3 FGF7 FGF10 FGF22 FGF4 FGF5 FGF6 FGF8 FGF17 FGF18 FGF9 FGF16 FGF20 FGF19 FGF

25、21 FGF23E K F N L P P G N Y K K P K L L Y C G S G A F P P G H F K D P K R L Y C G G V Y E H L G G A P R R R K L Y C R S Y D Y M E G G D I R V R R L F C V R S Y N H L Q G D V R W R K L F S P R S Y P H L E G D V R W R R L

26、F S S G A G D Y L L G I K R L R R L Y C Q S S F Q W S P S G R R T G S L Y C N W E S G Y L V G I K R Q R R L Y C L V T D Q L S R R L I R T Y Q L Y S A M T D Q L S R R Q I R E Y Q L Y S R A R D D V S R K Q L R L Y Q L Y S

27、V T D L D H L K G I L R R R Q L Y C P T D F A H L K G I L R R R Q L Y C A A Q L A H L H G I L R R R Q L Y C P H V H Y G W G D P I R L R H L Y T S S P L L Q F G G Q V R Q R Y L Y T N A S P L L G S S W G G L I H L Y T14 37

28、 34 55 68 31 72 67 74 42 43 43 49 48 52 33 35 2731 34 51 72 85 48 89 84 91 59 60 60 66 65 69 50 52 44bβ1C terminusN terminusβ9β8β6 β4 β7β5 β3β2β10β11β1 β12FGFR1. At least three genetic disorders can be attributed to mut

29、ations in FGFR1: Kallman’s syndrome36, osteo glophonic dyplasia and Pfeiffer’s syndrome37. Pathological FGFR1 sig- nalling also occurs in various malignancies. Glioblastoma brain tumours exhibit FGFR1 kinase domain gai

30、n-of- function mutations38, and FGFR1 is abnormally activated CraniosynostosisThis condition results from the premature closure of sutures of a developing skull before the completion of brain growth. The brain continues

31、to grow in areas of the skull where sutures have not closed, leading to a malformed cranium.Apert’s syndromeOne of the most common craniosynostosis syndromes that exhibits severe syndactyly (digit fusion) of the hands an

32、d feet. Apert’s syndrome is often associated with visceral abnormalities of the cardiovascular, respiratory and urogenital systems.Osteoglophonic dysplasiaA bone disorder presenting with dwarfism, vertebral fragility,

33、craniosynostosis and failure to thrive. The term osteoglophonic refers to the ‘hollowed out’ appearance of the metaphyses in X-rays, which are the growth zones of long bones. Pfeiffer’s syndromeA craniosynostosis disor

34、der that can also present with polydactyly.GlioblastomaAn aggressive tumour derived from glial cells that exhibits high levels of neovascularization.Modulators of FGF signalling. FGF-binding protein (FGFBP) is a carr

35、ier protein27 that activates FGFs by releasing them from the extracellular matrix, where they are bound by HSGAGs28. FGFBP has been shown to increase FGF2-dependent proliferation of fibroblast cells29 and may have an

36、 important role in the development of some cancers30. other activators of FGF signalling include fibronectin leucine-rich transmembrane pro- tein 3 (FLRT3), which facilitates FGF8 activity through the mAPK pathway31. T

37、he sprouty family of proteins play an important part in inhibiting receptor tyrosine kinase (RTK) signalling and were first discovered as inhibitors of FGFs in Drosophila melanogaster32. FGF signalling activates sprout

38、y proteins, which can then in turn inhibit FGF stimulation of the mAPK pathway by interacting with GRB2 (growth fac- tor receptor bound protein 2), SoS1 or RAF1 (REF. 33). mKP3 (mAPK phosphatase 3) is another general

39、inhibitor of RTK signalling that also impinges on FGF activity by dephosphorylating extracellular signal- regulated kinase (ERK)34. SEF is a specific inhibitor of FGFs that can function at multiple points along the sig

40、nalling pathway to attenuate signalling34.FGFR pathophysiology and therapy Germline gain-of-function mutations in FGFRs are responsible for various diseases, such as craniosynostosis, dwarfing syndromes and cancer. mos

41、t of the FGFR mutations are ligand independent, but a few — such as Ser252Trp and Pro253Arg in the ectodomain of FGFR2 — manifest only during ligand binding. These mutations cause Apert’s syndrome by enhancing ligand

42、 binding affinity and promoting the binding of inappro- priate ligands35,278–280. Remarkably, many of the germline mutations that cause skeletal syndromes also contrib- ute, through somatic mutations, to the developmen

43、t of cancer. Furthermore, mutations in FGFR1–FGFR3 often occur in homologous residues and account for multiple pathologies.Figure 1 | structural features of fibroblast growth factors (FgFs). a | FGF1, showing its 12

44、antiparallel β-sheets and amino and carboxyl termini. b | The 18 FGFs, grouped according to subfamily. The sequence alignment in the region of the divergent N terminus proximal to the β-trefoil core is given. The

45、β1 strand of FGF1 is provided to indicate the limit of the N terminus. c | FGF19 superimposed onto FGF2 from the FGF2–FGF receptor 1–heparin ternary structure (Protein Data Bank). FGF2 and FGF19 are rendered as ribb

46、ons and heparin is shown as sticks: oxygen (red), nitrogen (blue), carbon (beige), and sulphur (green) atoms are shown. The core regions of both ligands are coloured grey, and the heparin binding regions of FGF2 and

47、 FGF19 are coloured cyan and orange, respectively. Heparin from 1FQ9 clashes with the ridges in the heparin binding region of FGF19. To eliminate these clashes, heparin must translocate away from FGF19 but, in doing

48、 so, crucial contacts between heparin and the FGF19 backbone cannot be made. The weakened heparin binding observed in the FGF19 subfamily members is responsible for their endocrine behaviour.REVIEWSNATuRE REvIEwS |