# A Network Map of FGF-1/FGFR Signaling System

Authors: Rajesh Raju; Shyam Mohan Palapetta; Varot K. Sandhya; Apeksha Sahu; Abbas Alipoor; Lavanya Balakrishnan; Jayshree Advani; Bijesh George; K. Ramachandra Kini; N. P. Geetha; H. S. Prakash; T. S. Keshava Prasad; Yu-Jung Chang; Linyi Chen; Akhilesh Pandey; Harsha Gowda
Journal: Journal of Signal Transduction
 (2014)

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## 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.


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## Body

## 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 Table1. 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.


## 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].


## 3.1.1. 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.



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*Source: 962962-2014-04-16.xml*