Functional module | Gene symbol | Description | Network position | Up in | Function/potential role in disease |
---|---|---|---|---|---|
Cell cycle | BUB3 | BUB3 mitotic checkpoint protein | - | Early SSc-PF/NSIP | Encodes a mitotic cell cycle checkpoint protein that regulates the onset of anaphase |
CDC7 | Cell division cycle 7 | - | - | Regulates MCM complex | |
MCM3 | Minichromosome maintenance complex component 3 | - | Early SSc-PF/NSIP | Subunit of minichromosome maintenance (MCM) complex | |
MSH6 | MutS homolog 6 | - | Early SSc-PF/NSIP | Participates in DNA mismatch repair. | |
ECM disassembly/wound healing | CD44 | CD44 molecule (Indian blood group) | Bridge | - | A hyaluronic acid receptor that can interact with many other ligands found in the ECM. Primary idiopathic PF fibroblasts exhibit an invasive phenotype that was abrogated with treatment with anti-CD44 [39] |
CD63 | CD63 molecule | - | - | Has been observed to interact with TIMP1 [83] | |
CTSB | Cathepsin B | - | - | Regulates NPC2 secretion, TNF-alpha production, and cholesterol trafficking genes in an animal model of obesity [51] | |
CTSL | Cathepsin L | - | - | Regulates NPC2 secretion, TNF-alpha production, and cholesterol trafficking genes in an animal model of obesity [51] | |
GLB1 | Galactosidase, beta 1 | - | Early SSc-PF/NSIP | Mutations in this gene can lead to GM1-gangliosidosis, a manifestation of which includes foam cell accumulation in the lungs [84] | |
NPC2 | Niemann-Pick disease, type C2 | Hub | Early SSc-PF/NSIP | Mutations in this gene result in a lipid storage disorder. Functions in the regulation of cholesterol trafficking through the lysosome by binding to cholesterol released from low density lipoproteins taken up by cells | |
TGFBI | Transforming growth factor, beta-induced | Bridge | Late SSc-PF/UIP | Induced by phagocytosis of apoptotic debris in monocyte-derived MØs and regulates collagen turnover [44] | |
TIMP1 | TIMP metallopeptidase inhibitor 1 | - | Early SSc-PF/NSIP | Has been observed to interact with CD63 and overexpression has been noted to inhibit apoptosis in a CD63-dependent manner [83] | |
Innate immune response/NFkB signaling/apoptotic process | BIRC3 | Baculoviral IAP repeat-containing protein 3 | - | Late SSc-PF/UIP | Has antiapoptotic activity through interactions with caspases as well as the TNF superfamily members TRAF1 and TRAF2 [85, 86] |
CYR61 | Cysteine-rich, angiogenic inducer, 61 | Late SSc-PF/UIP | Also known as CCN1. Implicated in apoptosis in fibroblasts [87]. Has been shown to play a role in Fas-mediated and TRAIL-induced apoptosis [88, 89] | ||
DUSP6 | Dual specificity phosphatase 6 | - | Late SSc-PF/UIP | Plays a role in the positive regulation of apoptosis [90] | |
FAS | Fas cell surface death receptor | - | Early SSc-PF/NSIP | Cell surface death receptor | |
NFKBIE | Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon | - | - | Negative regulator of NFkB signaling | |
PLAUR | Plasminogen activator, urokinase receptor | Bridge | Late SSc-PF/UIP | Also known as uPAR. Contains an SSc risk SNP. Pulmonary fibroblasts from patients with idiopathic PF over express uPAR and that uPAR ligation results in a hypermotile phenotype [40] | |
PLSCR1 | Phospholipid scramblase 1 | - | - | Regulates phospholipid membrane asymmetry | |
TNFAIP3 | Tumor necrosis factor, alpha-induced protein 3 | Hub | Also known as A20. Contains an SSc risk SNP (also associated with other autoimmune conditions). Negative regulator of NFkB signaling | ||
TNFSF10 | Tumor necrosis factor (ligand) superfamily, member 10 | Bridge | - | Also known as TRAIL. Elevated in serum of SSc patients [91] | |
TNFRSF10B | Tumor necrosis factor receptor superfamily, member 10b | - | Late SSc-PF/UIP | Also known as TRAILR2 | |
IFN/antigen presentation | HLA-E | Major histocompatibility complex, class I, E | - | - | Class I MHC molecule |
HLA-F | Major histocompatibility complex, class I, F | - | - | Class I MHC molecule | |
IFITM1 | IFN induced transmembrane protein 1 | - | SSc-PF (UIP and NSIP) | IFN signaling | |
IFITM2 | IFN induced transmembrane protein 2 | - | Early SSc-PF/NSIP | IFN signaling | |
IFITM3 | IFN induced transmembrane protein 3 | - | Early SSc-PF/NSIP | IFN signaling | |
IRF1 | IFN regulatory factor 1 | - | Late SSc-PF/UIP | Activator of type I IFN signaling | |
OAS1 | 2′-5′-Oligoadenylate synthetase 1, 40/46 kDa | - | Early SSc-PF/NSIP | Involved in innate immune response to viral infection | |
Response to TGF-beta | CAV1 | Caveolin 1 | - | - | Contains an SSc risk SNP |
CTGF | Connective tissue growth factor | - | - | Also known as CCN2. Has been shown to play a role in Fas-mediated and TRAIL-induced apoptosis [88, 89] | |
DAB2 | Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila) | - | SSc-PF (UIP and NSIP) | Required for the epithelial to mesenchymal transition induced by TGF-beta in mouse and for type II TGFbR recycling [92, 93] | |
FN1 | Fibronectin 1 | - | - | Extracellular matrix protein. | |
LAMC1 | Laminin gamma1 chain | Hub | Early SSc-PF/NSIP | Expression of this gene is essential for the development of basement membranes [94] | |
THBS1 | Thrombospondin 1 | - | - | Mediates cell-to-cell and cell-to-matrix interactions. Putative biomarker of modified Rodnan skin score [95] |