Journal of Signal TransductionVolume 2014 (2014), Article ID 962962, 16 pageshttp://dx.doi.org/10.1155/2014/962962

Review Article

A Network Map of FGF-1/FGFR Signaling System

Rajesh Raju,¹ Shyam Mohan Palapetta,1,2 Varot K. Sandhya,¹ Apeksha Sahu,1,2 Abbas Alipoor,³ Lavanya Balakrishnan,¹ Jayshree Advani,¹ Bijesh George,¹ K. Ramachandra Kini,³ N. P. Geetha,³ H. S. Prakash,³ T. S. Keshava Prasad,¹ Yu-Jung Chang,⁴ Linyi Chen,⁴ Akhilesh Pandey,5,6,7,8 and Harsha Gowda¹

¹Institute of Bioinformatics, International Tech Park, Bangalore 560066, India²Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry 605014, India³Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore 570006, India⁴Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan⁵McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA⁶Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA⁷Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA⁸Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Received 20 November 2013; Accepted 3 March 2014; Published 16 April 2014

Academic Editor: Shoukat Dedhar

Copyright © 2014 Rajesh Raju et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Fibroblast growth factor-1 (FGF-1) is a well characterized growth factor among the 22 members of the FGF superfamily in humans. It binds to all the four known FGF receptors and regulates a plethora of functions including cell growth, proliferation, migration, differentiation, and survival in different cell types. FGF-1 is involved in the regulation of diverse physiological processes such as development, angiogenesis, wound healing, adipogenesis, and neurogenesis. Deregulation of FGF-1 signaling is not only implicated in tumorigenesis but also is associated with tumor invasion and metastasis. Given the biomedical significance of FGFs and the fact that individual FGFs have different roles in diverse physiological processes, the analysis of signaling pathways induced by the binding of specific FGFs to their cognate receptors demands more focused efforts. Currently, there are no resources in the public domain that facilitate the analysis of signaling pathways induced by individual FGFs in the FGF/FGFR signaling system. Towards this, we have developed a resource of signaling reactions triggered by FGF-1/FGFR system in various cell types/tissues. The pathway data and the reaction map are made available for download in different community standard data exchange formats through NetPath and NetSlim signaling pathway resources.

1. Introduction

Fibroblast growth factor (FGF) superfamily consists of structurally related polypeptides most of which function through its high affinity fibroblast growth factor receptors (FGFRs). In addition to FGFRs, they also bind to heparan sulfate proteoglycans (HPSGs) and their analog, heparin. These interactions influence the stability of FGFs in the extracellular matrix and also regulate their binding and activation of FGFRs [1–9]. In humans, FGFs are encoded by 22 genes, FGF-1-14 and FGF-16-23, and are divided into 7 subfamilies. FGFs 1–10 and 16–23 are FGFR ligands, while FGFs 11–14 are intracellular FGF homologous factors which act in a receptor-independent fashion [10]. Knock-out mice of different FGFs exhibit diverse developmental and physiological disorders [11]. For instance, FGF-9 is involved in the development of lung and testes [12, 13], FGF-3 is critical for inner ear development [14], and FGF-18 is important in bone and lung development [15–17]. Moreover, knock-out of FGFs 4, 8, 9, 10, 15, 18, or 23 was found to be lethal in mice [18]. FGFs are also involved in wound healing, tissue repair [19, 20], and angiogenesis [21]. Facilitating cell proliferation, migration, and differentiation [16, 22–26], FGFs are implicated in diverse pathological conditions including cancer [27] as well as metabolic and developmental disorders [18].

Most FGFs have an N-terminal signal peptide and are thus secreted. FGFs 1, 2, 9, 16, and 20 do not have signal peptides. FGFs 9, 16, and 20 may be released through classical secretory pathway; however, FGF-1 and FGF-2 are released from damaged cells or through endoplasmic reticulum-golgi independent exocytotic pathway [10]. FGF-1 along with FGF-2 was initially isolated from bovine pituitary extracts based on their ability to induce proliferation in 3T3 fibroblasts [28, 29]. Also known as acidic FGF, FGF-1 is a 155 amino acid long non-glycosylated polypeptide. FGF-1 is not released from the cells under normal physiological conditions, but it was secreted in response to stress conditions such as heat shock, hypoxia [30, 31], serum starvation [32], and exposure to low-density lipoproteins [33]. Stress induces the release of inactive disulfide bond-linked homodimeric form of FGF-1, which is dependent on p40-Syt1, S100A13, and Cu²⁺ ions [34–37]. FGF-1 has been shown to reduce apoptosis in vascular injury [38–40]. Administration of FGF-1 has shown promise as a therapeutic strategy against human cervical spinal cord injury [41] and ischemic conditions [42–44]. Increased expression of FGF-1 was observed in ovarian [45] and prostate cancers [46]. Taken together, FGF1 is involved in different cellular functions that are mediated through its interaction with the four FGF receptors [47, 48]. A pathway resource representing these diverse functions and the underlying mechanisms that regulate these processes would be immensely useful.

Curated pathway maps are invaluable resources for scientific community. Such comprehensive pathway datasets are being increasingly used in bioinformatics efforts directed towards analysis of high-throughput datasets from various disease contexts. Repositories including Pathway Interaction Database of the National Cancer Institute (http://pid.nci.nih.gov/), Database of Cell Signaling (http://stke.sciencemag.org/cm/), KEGG Pathway Database (http://www.genome.jp/kegg/pathway.html), and INOH Pathway Database (http://inoh.org/) have cataloged basic components of FGF signaling. We have expanded the scope of this by providing a comprehensive representation of FGF1 signaling pathway and its diverse roles in regulating various cellular processes.

2. Methodology

Documentation of specific pathway reactions scattered in the literature into an organized, user-friendly, query-enabled platform is primary to the analysis of signaling pathways. We used NCBI PubMed database to carry out an extensive literature search to retrieve research articles where molecular events triggered by the FGF-1/FGFR signaling system were studied. Specific molecular events screened include (a) physical associations between proteins, (b) posttranslational modifications (PTMs), (c) change in subcellular localization of proteins, (d) activation or inhibition of specific proteins, and (e) regulation of gene expression. Relevant information from research articles were manually documented using the curation tool, PathBuilder. To streamline and organize data collection from literature, we followed the previously described criteria for the inclusion/exclusion of pathway specific reactions [49, 50]. The data accumulated was submitted to the NetPath signaling pathway resource developed by our group [51]. We then generated a signaling map for this pathway using PathVisio pathway visualization software. We also applied additional criteria to filter out low confidence reactions from the gathered data [52] and generated a NetSlim map. In addition to curation of molecular level information, we have also cataloged physiological effects brought about by FGF-1 in different cell types/tissues.

3. Results and Discussion

Canonical FGF/FGFR signaling reactions have been documented in a few public repositories and review articles. Vast amount of literature in the last few years have revealed several novel pathway intermediates of FGF/FGFR signaling system. In order to generate a comprehensive view of FGF/FGFR signaling pathway, we carried out extensive literature search on PubMed for articles pertaining to FGF-1 signaling. Of a total of 3275 articles that were screened, 237 of them had molecular reactions reported downstream of FGF-1 in various cell types/tissues. Manual curation from these research articles revealed 109 molecules involved in FGF-1 induced physical associations, modulation by PTMs, activity, and subcellular or cell surface translocation events. Of the 42 physical associations that were cataloged, 29 were “binary” and 13 were “complex” interactions inclusive of the ligand/receptor interactors. We could record a total of 87 catalysis events, 15 activation/inhibition, and 21 translocation events. The 87 catalysis events include 19 events, where the enzymes directly catalyzing the reactions were studied and reported, and 68 events for which the enzymes which post-translationally modified the proteins are not studied under FGF-1 stimulation. Apart from these molecular reactions, we have also cataloged 117 genes whose expression is reported to be either upregulated or downregulated by FGF-1 treatment. However, only a total of 25 genes were reported to be differentially regulated at mRNA level by FGF-1 stimulation in different human cell types. A list of genes reported to be regulated by FGF-1 in different mammalian systems at the mRNA and/or the protein level is provided in Table 1. After the annotation process, all the entries were reviewed and approved by internal reviewers. Internally reviewed pathways were further reviewed and approved by an external pathway authority (LC, who is an author in this paper).

Table 1: List of genes that are reported to be transcriptionally and translationally regulated by FGF-1 in humans and other mammals.

Gene symbol
Up-/down regulation
mRNA/Protein
Experiment
Organism
Tissue/cell line/type
PubMed ID
Transcriptional regulator
Regulator Gene ID
PubMed ID

1
APOE
Up
mRNA and protein
RT-PCR, Western blot
Rat
Astrocytes
18216067, 19229075, 17548887, 15627653

2
BAMBI
Down
mRNA and protein
RT-PCR, Western blot
Human
Preadipocytes
22187378

3
CCND1
Up
mRNA and protein
Gene chip array, Western blot
Human, rat
MG63 osteoblastic cells, Rat Wister bladder tumor cells (NBT-II)
15572039, 18189245

4
CDK5R1
Up
mRNA and protein
Q-PCR, Western blot
Rat
PC12 cells
19249349

5
CDKN1A
Up
mRNA and protein
RT-PCR, Western blot
Human, mouse, rat
Chondrocytes, REtsAF cells
16091747, 16153144, 11779141, 10364154
STAT1
6772
11779141, 10364154

6
CEBPA
Up
mRNA and protein
RT-PCR, Western blot
Human, mouse
Preadipocytes, 3T3-L1 cells
17068114

7
CEBPB
Up
mRNA and protein
RT-PCR, Western blot
Human, mouse
Preadipocytes, 3T3-L1 cells
17068114

8
COX2
Up
mRNA and protein
Northern blot, ELISA
Human, rabbit
Cardiac muscle microvessel endothelial cells
8790580, 2107185

9
EGR1
Up
mRNA and protein
Q-PCR, Western blot
Mouse, rat
PC12 cells, Hippocampal neuronal cell line HT22, human periodontal ligament cells
19249349, 20649566, 18179472, 24396070
STAT3, SP1
6774, 6667
24396070

10
FOS
Up
mRNA and protein
RT-PCR, northern blot (mouse and rat), Immunohistochemistry, Western blot
Mouse, rat, human
3T3 cells, Adipocytes, ENU1564 cell, Astrocytes of periventricular zone of third ventricle, SUM-52PE cells
16309174, 2507555, 18041768, 11172932, 20388777

11
JUN
Up
mRNA and protein
RT-PCR, Western blot
Rat
ENU1564 cells
18041768

12
JUNB
Up
mRNA and protein
Gene chip array (Rat), Western blot
Rat, human
Rat Wister bladder tumor cells (NBT-II), SUM-52PE cells
18189245, 20388777

13
MDM2
Up
mRNA and protein
RT-PCR, Western blot
Rat
REtsAF cells
16091747

14
MMP14
Up
mRNA and protein
Northern blot, Gene chip array, Western blot
Human, rat
Prostate cancer cell line, LNCaP, Rat Wister bladder tumor cells (NBT-II)
14673954, 18189245
STAT3
6774
14673954

15
MMP9
Up
mRNA and protein
RT-PCR, Gene chip array, Western blot
Rat
ENU1564 cells, Rat Wister bladder tumor cells (NBT-II)
18041768, 18189245
RELA, JUN, FOS
5970, 3725, 2353
18041768

16
MYC
Up
mRNA and protein
Northern blot (Mouse), Western blot
Mouse, human
3T3 cells, SUM-52PE cells
16309174, 20388777

17
NOS2
Up
mRNA and protein
RT-PCR, Western blot
Rat
Astrocytes
16524372

18
PLAU
Up
mRNA and protein
RT-PCR, ELISA
Human
Fibroblasts
12008951

19
PPARG
Up
mRNA and protein
RT-PCR, Western blot
Human, mouse
Preadipocytes, 3T3-L1 cells
17068114, 22187378

20
SLC2A4
Up
mRNA and protein
RT-PCR, Western blot
Human, mouse
Preadipocytes, 3T3-L1 cells
22187378, 17068114

21
THY1
Up
mRNA and protein
Northern blot, Western blot
Rat
PC12 cell lines
11084019

22
TNFRSF12A
Up
mRNA and protein
RT-PCR, Immunoblot
Rat
Cardiomyocytes
19629561

23
NGF
Up
mRNA and Protein
RT-PCR, Enzyme Immuno assay
Rat
Hippocampal astrocytes, skin fibroblasts, Primary spinal cord astrocyte
1377078, 15773903

24
VEGFA
Up
mRNA and protein
Real time PCR, ELISA
Human
Primary human airway smooth muscle cells
22205500

25
ACPL2
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

26
ARG1
Up
mRNA
Gene chip array, Q-PCR
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

27
ATP2A2
Up
mRNA
RNA gel blot
Mouse
NIH 3T3 cells
7506544

28
AXIN2
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

29
BGLAP
Up
mRNA
in situ hybridization
Mouse
Mouse calvaria cells (coronal sutures)
12674336

30
CTSC
Up
mRNA
Gene chip array
Rat
Rat wister bladder tumor cells (NBT-II)
18189245

31
DKK3
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

32
DLL1
Down
mRNA
Northern blot
Mouse
Neuroepithelial precursor (E10)
11466430

33
DUSP1
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

34
DYNC2LI1
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

35
EDNRA
Up
mRNA
Northern blot
Rat
Arterial smooth muscle cells
12851419

36
EFNB1
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

37
ELF4
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

38
FASN
Up
mRNA
RNA gel blot
Mouse
NIH 3T3 cells
7506544

39
FGF1
Up
mRNA
RT-PCR
Rat
Pheochromocytoma cells
8576258

40
FGF7
Up
mRNA
RT-PCR
Mouse
Embryonic lung mesenchymal cells
10446271

41
FN1
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

42
FZD1
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

43
FZD2
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

44
FZD7
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

45
FZD8
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

46
F3
Down
mRNA
Northern blot
Human
Human umbilical vein endothelial cells
9157959

47
GADD45A
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

48
HBEGF
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

49
HMGA2
Down
mRNA
Northern blot
Rat
3T3-L1 cells
10490844

50
IBSP
Up
mRNA
in situ hybridization
Mouse
Mouse calvaria cells (coronal sutures)
12674336

51
IGF1
Down
mRNA
RT-PCR
Human
Fibroblasts
12008951

52
IGF2
Down
mRNA
RT-PCR
Human
Fibroblasts
12008951

53
IGF1R
Down
mRNA
RT-PCR
Human
Fibroblasts
12008951

54
IGF2R
Down
mRNA
RT-PCR
Human
Fibroblasts
12008951

55
IGFBP4
Down
mRNA
RT-PCR
Human
Fibroblasts
12008951

56
IL4
Up
mRNA
Q-PCR
Rat
Transected spinal cord tissue
21411654

57
IRS1
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

58
LAMA3
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

59
LRRC17
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

60
MITF
Up
mRNA
Microarray
Mouse
Osteoblast cells
18505824

61
MMP13
Up
mRNA
Gene chip array, Q-PCR
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

62
MMP3
Up
mRNA
Northern blot
Rat
PC12 cell lines
11084019

63
MSH6
Up
mRNA
RNA gel blot
Mouse
NIH 3T3 cells
8870641

64
MSX2
Up
mRNA
in situ hybridization
Mouse
Mouse calvaria cells
12674336

65
NID2
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

66
NOTCH1
Up
mRNA
Northern blot, Gene chip array, Q-PCR
Mouse, rat
Neuroepithelial precursor (E10), bladder tumor cells (NBT-II)
11466430, 18189245

67
NR1H3
Up
mRNA
RT-PCR
Rat
Astrocytes
19229075

68
ODC1
Up
mRNA
Northern blot
Mouse
NIH 3T3 cells
9223379

69
PDGFA
Up
mRNA
RNA gel blot
Human
HUVE cells
1689299

70
PFKL
Up
mRNA
RNA gel blot
Mouse
NIH 3T3 cells
7506544

71
PLAT
Up
mRNA
RT-PCR
Human
Fibroblasts
12008951

72
PLAUR
Up
mRNA
RT-PCR
Human
Fibroblasts
12008951

73
PLF
Up
mRNA
Northern blot
Mouse
NIH 3T3 cells
9223379

74
PMEPA1
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

75
PNRC1
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

76
POSTN
Up
mRNA
Northern blot
Rat
Pulmonary arterial smooth muscle cells
15121739

77
PPIA
Up
mRNA
Northern blot
Rat
PC12 cell lines
11084019

78
PRICKLE1
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

79
PRPH
Up
mRNA
Northern blot
Rat
PC12 cell lines
11084019

80
PTPRE
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

81
RUNX2
Up
mRNA
in situ hybridization
Mouse
Mouse calvaria cells (coronal sutures)
12674336

82
SCGB1A1
Up
mRNA
RT-PCR
Mouse
Mouse lung epithelium
12242715

83
SDC1
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

84
SERPINB1
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

85
SERPINB2
Up
mRNA
RT-PCR
Human
Fibroblasts
12008951

86
SERPINE1
Up
mRNA
RT-PCR
Human
Fibroblasts
12008951

87
SFRP1
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

88
SFTPC
Up
mRNA
RT-PCR
Mouse
Mouse lung epithelium, Embryonic stem cell (mESC) line E14-Tg2a
12242715, 20497026

89
SOCS1
Up
mRNA
Northern blot
Rat
Mouse lens epithelium
14985304

90
SOCS3
Up
mRNA
Northern blot
Rat
Mouse lens epithelium
14985304

91
SOX2
Up
mRNA
Microarray
Mouse
Osteoblast cells
18505824

92
SPP1
Up
mRNA
Quantitative northern blot
Rat
Pulmonary arterial smooth muscle cells
15121739

93
SPRY1
Up
mRNA
RNA gel blot
Mouse
MC3T3-E1 osteoblasts
16604287

94
SPRY2
Up
mRNA
RNA gel blot
Mouse
MC3T3-E1 osteoblasts
16604287

95
SPRY4
Up
mRNA
RNA gel blot
Mouse
MC3T3-E1 osteoblasts
16604287

96
S1PR3
Up
mRNA
Northern blot
Human
Human umbilical vein endothelial cells
9315732

97
TCF3
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

98
TCF4
Down
mRNA
RT-PCR
Human
Preadipocytes
22187378

99
TGFA
Up
mRNA
Northern blot
Mouse
Cultured keratinocytes
7535082

100
TGFB2
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

101
TGFBR3
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

102
THBS1
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

103
THBS1
Up
mRNA
Northern blot
Mouse
NIH 3T3 cells
9223379

104
TIMP1
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

105
TIMP3
Down
mRNA
Microarray
Mouse
Osteoblast cells
18505824

106
VIM
Up
mRNA
Gene chip array
Rat
Rat Wister bladder tumor cells (NBT-II)
18189245

107
ADIPOQ
Up
Protein
Radioimmunoassay
Human
Preadipocytes
17068114

108
CCNE1
Up
Protein
Western blot
Human
MG63 osteoblastic cells
15572039

109
CTNNB1
Down
Protein
Western blot
Human
Simpson Golabi Behmel syndrome (SGBS), Preadipocytes
22187378

110
HMOX1
Up
Protein
Western blot
Human
Spinal cord astrocytes
16524372

111
MMP7
Up
Protein
ELISA
Human
LNCaP cells
11922392
STAT3
6774
11922392

112
PKMYT1
Up
Protein
Immunoblot
Rat
Chondrosarcoma cells
21051949

113
PLIN1
Up
Protein
Western blot
Human, mouse
Preadipocytes, 3T3-L1 cells
17068114

114
PTGIS
Down
Protein
ELISA
Human
Endothelial cells
2107185

115
PTGS2
Down
Protein
ELISA
Human
Endothelial cells
2107185

116
RELA
Up
Protein
Western blot
Rat
ENU1564 cells
18041768

117
RHOA
Up
Protein
Immunoblot
Rat
Cardiomyocytes
19629561

118
SOX9
Up
Protein
Western blot
Mouse
Costal chondrocytes
10655493

119
WEE1
Up
Protein
Immunoblot
Rat
Chondrosarcoma cells
21051949

120
CDH2
Up
Protein
Western blot
Rat
PC12 cells
24396070
STAT3, SP1
6774, 6667
24396070

121
GAP43
Up
Protein
Western blot
Rat
PC12 cells
24396070
STAT3
6774
24396070

3.1. Signaling Modules Activated by FGF-1

Signaling modules comprise a well-characterized group of molecules and their interactions downstream of activation of a receptor. We documented the following signaling modules to be activated upon stimulation with FGF-1.

3.1.1. Ras/Raf/Mek/Erk Pathway

The Ras/Raf/Mek/Erk pathway has been implicated in cellular processes including cell growth, proliferation, and migration. Stimulation of different cell types with FGF-1 resulted in the formation of multiple complexes involving FRS2, GAB1, SOS1, PTPN11, SHC1, SH2B1, and GRB2 [53–60]. These complexes are critical to the subsequent activation of Ras [53, 56]. Association of Ras with Raf kinase [53] induces autophosphorylation and activation of Raf. Activation of Raf leads to phosphorylation dependent activation of Map kinases 1/2 (MAP2K1/2) and subsequently Erk2/1 (MAPK1/3) [60–62]. In the context of FGF-1 signaling, this module was reported to be involved in a number of processes including neurogenesis, adipocyte differentiation, cell proliferation, cholesterogenesis, cardioprotection, and tumor invasion and metastasis [62–67].

3.1.2. Pi3k/Akt Pathway

The complexes mentioned above also lead to the activation of Pi3k/Akt pathway, another signaling module that regulates various processes including cell growth, survival, cell proliferation, and cell migration [68]. A number of studies have shown FGF-1 induced phosphorylation of Akt [63, 64, 69]. Pi3k inhibitor-based functional assays also proved the involvement of FGF-1 pathway in diverse physiological conditions including angiogenesis [70], lung development [71], maintenance of neuronal phenotype [72], neuroprotection [73], and ApoE-HDL secretion [69].

3.1.3. Jnk and p38 Mapk Pathway

The c-jun N-terminal kinase (Jnk) pathway is implicated in the regulation of cell cycle, cell survival and apoptosis. FGF-1 stimulates the phosphorylation of p38 Mapk (MAPK14) as well as Jnk1/2 (MAPK8/9). The Jnk1/2 was also found to be crucial to neurogenesis and vascular remodeling [63, 74]. The specific functions of FGF-1 signaling mediated by p38 Mapk include growth arrest, promotion of apoptosis in response to oxidative stress, and formation of actin stress fibers [75–77].

3.1.4. STAT3 and Nf-kb Pathway

FGF-1 also stimulates STATs (STAT1 and STAT3) and Nf-kB signaling modules. FGFR signaling is reported to be regulated through several downstream molecules including JAK2, SRC, SH2B1, MAPK1/3, MAPK8/9, and STAT3. This signaling axis is known to regulate various cellular processes including neurite outgrowth, cell proliferation, and increased cancer cell invasion [78–80]. In addition, FGF-1 is also reported to induce MMP9 expression in mammary adenocarcinoma cells through the Nf-kb pathway [81].

3.2. Physiological Effects Mediated by FGF-1

FGF-1 was found to be involved in a number of biological processes. It is associated with the development of heart [82], lens [83], lung, and liver [84–86]. Its crucial roles in neurogenesis as well as adipogenesis [65, 87, 88] have also been reported. FGF-1 induces growth arrest and differentiation in chondrocytes [89–92]. It is implicated in angiogenesis [93–95] and wound healing [95–99]. Multiple studies have also shown the role of FGF-1 in cardioprotection [99–101] and neuroprotection [22, 102]. FGF-1 also induces migration [103–105] and proliferation [106–108] in different types of cancer cells. It is also involved in the regulation of epithelial-to-mesenchymal transition [109, 110], and tumorigenesis [111] as well as invasion and metastasis [64, 112]. A list of functional effects of FGF-1 studied in different cell types/tissues is provided in Table 2.

Table 2: Functions of FGF-1 identified in diverse cell/tissue types of human and other mammalian origins.

Function
PubMed ID
Cell type/tissue
Organism

Adipogenesis
22187378, 17068114
Preadipocytes
Human

Apoptosis
20657013
Hepatoma cells, HEK293 cells
Human

15773903
Motor neuron
Rat

9681989
Peroxynitrite-induced apoptosis in PC12 cells
Rat

Cell cycle arrest
16153144
cells
Human

Cell migration
9108375
Skin fibroblasts
Human

11019781
Fibroblasts
Mouse

Cell proliferation
9182757
Embryo fibroblasts
Rat

2441696
Arterial smooth muscle cells
Human

14966081
AT2 alveolar cells
Human

15094393
Human long-bone growth plate chondrocytes
Human

1699952
Umbilical vein endothelial ceils
Human

15767480
Y79 cells
Human

2303528
Epidermal keratinocytes (BALB-MK1)
Mouse

2303528
Keratinocytes (BALB/MK-1)
Mouse

2383402
Leydig cells (TM3)
Mouse

1379845
Megakaryocyte progenitor cells
Mouse

1379845
Megakaryocytes
Mouse

14985304
Murine lens epithelial cell lines CRLE2, 1AMLE6, TN4-1 and NKR11
Mouse

15574884
NIH-3T3 cells
Mouse

3272188
Adrenal chromaffin cells
Rat

2566605
Astroblasts
Rat

1377078
Hippocampal astrocytes
Rat

2153969
Rat bladder carcinoma cell line (NBT-II)
Rat

8622701
PC12 cells
Rat

8732667
Prostate cancer cells
Rat

1638984
Retinal cells
Rat

1377078
Skin fibroblasts
Rat

12907464
Aortic smooth muscle cells
Human, rat

1638984
Retinal cells
Rats

22108586
Periodontal fibroblasts
Rat

3272188
Adrenal chromaffin cells
Rat

22108586
Periodontal ligament fibroblasts
Rat

20388777
SUM-52PE cells
Human

Cell rounding, growth inhibition
11779141
ATDC5 cells, chondroprogenitor cell lines
Mouse

Cholesterol biosynthesis
19713443
Mouse fibroblasts and rat astrocytes
Mouse, rat

19229075
Astrocytes
Rat

18216067
Astrocytes
Rat

17548887
Astrocytes
Rat

Differentiation
20497026
Embryonic stem cell (mESC) line E14-Tg2a
Mouse

Epithelial-mesenchymal transition
2153969
NBT-II cells (Rat bladder carcinoma cell line)
Rat

7593195
NBT-II
Rat

2153969
NBT-II
Rat

Fiber cell differentiation
7539358
Lens epithelial cells
Mouse

G0/G1 arrest
21051949
Chondrosarcoma cells
Rat

G2 arrest
21051949
Chondrosarcoma cells
Rat

G2/M transition
20044603
Breast cancer cells
Human

Growth arrest
14593093
Rat chondrosarcoma (RCS) cells
Rat

Inhibition of apoptosis
16524372
Astrocytes
Rat

17473910, 16091747
PC12 and RetsAF cells
Rat

Inhibition of cell growth
17363592
TAKA-1 cells
Hamster

Inhibition of neurogenesis
11466430
NEP cells
Mouse

Inhibition of proliferation
10364154
Chondrosarcoma cells (RCS)
Rat

Membrane ruffling
7534069
Human ductal breast epithelial tumor cell line (T47D)
Human

Neurite outgrowth
20175207
TREX 293 cells
Human

3272188
Adrenal chromaffin cells
Rat

8764646
PC12 cells
Rat

19249349
PC12 cells
Rat

3316527, 8576258
PC12 cells
Rat

12127979, 9182757, 2157719
PC12 cells
Rat

Neuronal differentiation
16716298
Primary astrocyte from human fetal brain
Human

7514169, 8622701, 2157719
PC12 cells
Rat

Osteoblast proliferation
18041768
ENU1564 cells
Rat

Osteoblast differentiation
18505824
Osteoblasts
Mouse

Osteogenic differentiation
12674336
Sutural mesenchyme in mouse calvaria
Mouse

Protection from apoptosis
19765618, 8576258
PC12 cells
Rat

Repression of myogenic differentiation
1379245
Skeletal muscle myoblasts (MM14)
Mouse

Retinal cell proliferation
15978261
Retinal cells
Mouse

Skeletal muscle development
8601591
Skeletal muscle myoblasts (MM14)
Mouse

Synaptic plasticity
20649566
Hippocampal neuronal cell line HT22
Mouse

Tumorigenesis
20889570
JMSU1 urothelial carcinoma cell lines
Human

9038374
NBD-II
Rat

Vascular remodeling
15121739
Pulmonary arterial smooth muscle cells (PASMCs)
Rat

22205500
ASM (Airway Smooth Muscle cells)
Human

Regeneration
3353388
Retinal ganglion cells
Rat

Astrocyte activation
15773903
Primary spinal cord astrocyte
Rat

Neurogenesis
20429889
Embryonic stem cells
Mouse

Wound healing
9036931

Mouse

Cord Formation
16631103

Rat

Decrease in food intake
7692459

Rat

Facilitation of memory
7692459

Rat

Increase in sleep duration
8985960

Rabbit

Maintenance of the integrity of the organ of corti, initiation of protective recovery and repair processes following damaging auditory stimuli
7568115

Rat

Arteriole dilation
8853345

Rat

Feeding suppressor function
11172932

Rat

Hair-cell innervation during the terminal development of the sensory epithelium
12792312

Rat

Lens regeneration
3792708

Bovine

Lung morphogenesis and differentiation
12242715

Rat

Metastasis
1707175

Rat

Muscle regeneration
1384586

Mouse

Myocardial remodeling
19629561

Rat

Neuroprotection
12095987

Rat

Prevention of premature angiogenesis and inflammatory responses
17643421

Mouse

Protection against hypoxic-ischemic injury
16635575

Rat

Spinal cord injury repair
21411654

Rat

Cardioprotection
15337227, 12176126

Mouse

3.3. Pathway Visualization, Data Formats, and Availability

User-friendly visualization of pathways is an important aspect to provide a concise view. A number of tools are available for visualization and analysis of pathway data including Cytoscape [113], ChisioBioPAX Editor (ChiBE) [114], visualization and layout services for BioPAX pathway models (VISIBIOweb) [115], and ingenuity pathway analysis. These tools use pathway and molecular interaction data in different XML-based community standard data exchange formats as input. These standard formats, which include Proteomics Standards Initiative for Molecular Interaction (PSI-MI version 2.5), Biological Pathway eXchange (BioPAX level 3), and Systems Biology Markup Language (SBML version 2.1), enable easy data exchange and interoperability with multiple software. We have provided the annotated pathway data in the standard formats mentioned above. This data can be downloaded and used from NetPath [51], an open source resource for signal transduction pathways developed by our group (http://www.netpath.org/index.html). Additionally, we have drawn a map of FGF-1/FGFR signaling using the data accumulated in NetPath. This network map represents the molecules and their reactions organized by topology and excludes the molecules identified through phosphoproteomics approaches for which topology could not be assigned (Figure 1). The map was manually drawn using freely available software, PathVisio [116]. The topology of the molecules and their reactions in the pathway was arranged based on (i) inhibitor-based assays, (ii) mutation-based assays, (iii) knock-out studies, (iv) prior knowledge of canonical modules, and/or (v) with reference to multiple review articles. Another map, which incorporated high confidence reactions in accordance with NetSlim criteria [52], is submitted to the NetSlim database. These maps can be visualized and downloaded in gpml, GenMAPP, png, and pdf formats from http://www.netpath.org/netslim/FGF-1_pathway.html. Each node in the map is linked to their molecule page in NetPath, thereby to other pathways in NetPath, and to HPRD [117] and RefSeq protein accessions. In the “map with citation” option, the edges connecting the nodes are linked to the corresponding articles in PubMed that report the FGF-1 stimulated reaction(s). Direct reactions are represented by solid edges. Indirect reactions are represented with dashed edges. The edges which represent the protein-protein interactions, enzyme-substrate reactions and translocation events are distinguished by different colors.

Figure 1: Network map of FGF-1 signaling. This map manually drawn using PathVisio [112] represents the reactions induced by FGF-1 through their receptors. Each node represents the molecules and the post-translationally modified states of proteins are also represented. Distinguished by color and continuous/dashed lines, the edges represent the specific information such as protein-protein interactions, enzyme-substrate reactions, reactions mediated through unknown/multiple steps, and protein translocations as provided in the legend. The biological processes that FGF-1 regulates through multiple signaling modules are also represented. A NetSlim [52] version of this map can be obtained from http://www.netpath.org/netslim/FGF-1_pathway.html.

4. Conclusions

Availability of specific ligand-receptor mediated signaling data in community approved formats is crucial to the understanding of proteins and their reactions in diverse biological processes. Analysis of high-throughput data obtained from microarray- and mass spectrometry-based platforms essentially relies on enrichment of biological function or signaling pathways available in databases to obtain insights into their physiological functions. Although some resources have cataloged FGF signaling in general, this is the first attempt to provide a comprehensive view of FGF-1 signaling. This will be extended to other FGF ligands and/or specific FGFRs in the future to facilitate the analysis of differences between different FGFs and/or FGFRs. The pathway information has been made available through NetPath and NetSlim resources in multiple community standard data formats. The FGF-1 signaling pathway data will be periodically updated in NetPath. We have cataloged multiple signaling modules that are activated upon activation of FGFR and their implications in diverse physiological and pathophysiological processes. We believe that the data presented here will boost further research in this area and will help identify novel therapeutically important molecules that could be targeted in pathological conditions involving aberrant FGF-1 signaling.

Abbreviations

S100A13: | S100 calcium binding protein A13
FRS2: | Fibroblast growth factor receptor substrate 2
GAB1: | GRB2-associated binding protein 1
SOS1: | Son of sevenless homolog 1
PTPN11: | Protein tyrosine phosphatase, non-receptor type 11
SHC1: | Src homology 2 domain containing transforming protein 1
GRB2: | Growth factor receptor-bound protein 2
Mapk: | Mitogen activated protein kinase
Pi3k: | Phosphatidylinositide 3-kinase
Akt: | v-akt murine thymoma viral oncogene homolog
HDL: | High density lipoprotein
Jnk: | Jun N-terminal kinase
STAT3: | Signal transducer and activator of transcription 3.

Conflict of Interests

The authors have no conflict of interests.

Authors’ Contribution

Shyam Mohan Palapetta, Varot K. Sandhya, and Apeksha Sahu contributed equally to the paper.

Acknowledgments

The authors thank the Department of Biotechnology (DBT), Government of India, for research support to the Institute of Bioinformatics, Bangalore. Shyam Mohan Palapetta is supported by a Senior Research Fellowship from the Council of Scientific and Industrial Research (CSIR), India. Varot K. Sandhya is a recipient of Inspire Fellowship from the Department of Science and Technology (DST), Government of India. Harsha Gowda is a Wellcome Trust/DBT India Alliance Early Career Fellow.

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