Table 1.
Lysyl oxidase (LOX) regulatory and cross-regulatory interactions with signaling pathways.
| Signaling Mediators | Interaction/Activity | Signaling Pathways Involved | Refs. |
|---|---|---|---|
| Ang II | Ang II upregulated LOX via EGFR transactivation | EGFR transactivator ADAM17, EGFR/PI3K/AKT, MEK/ERK and SAPK/JNK (lung carcinoma); Oxidative stress-activated p38MAPK (vascular remodeling) | [11,12,16] |
| EGFR | LOX-controlled modulation of EGFR cell surface availability and EGF activation | Suppressed TGF-β signaling leading to HTRA1/increased MATN2 that traps EGFR at cell surface (tumor progression) | [13] |
| PDGF | LOX-induced modification/oxidation of cell surface PDGFRβ | Faster turnover of PDGFR-dependent SHP2, AKT1, ERK1/2 (chemotactic response); PDGF/TGF-β1/ERK1/2 (vascular remodeling, myelofibrosis); PDGFRβ/Akt/VEGF (angiogenesis) |
[17,18,19,20,22] |
| VEGF | Mutual positive regulation | LOX-activated AKT via PDGFRβ/increased VEGF (endothelial cells, hepatocellular carcinoma, diabetic neovascularization); VEGF-promoted LOX activity via Akt/ERK/JNK/p38/NF-κB (endothelial angiogenesis) |
[22,26,27,28,29,30] |
| Cu-related coregulation | VEGF/LOX upregulation by Cu-dependent activation of HIF-1α (angiogenesis); VEGF/LOX expression coordinated with HIF-1α by DAC2 | [34] | |
| TGF-β | Coregulation of LOX with ECM substrates | TGF-β/p38MAPK via TGF-β response promoter elements in the LOX and the COL1A1/A2 genes | [37] |
| Induction of LOX gene expression | TGF-β and TGF-βR1; PI3K, Smad3, p38-MAPK, JNK, ERK1/2 (fibrosis); Smad2/3 promoted C-JUN/AP-1 (myocardial fibrosis); TGF-β/SMAD3 (preeclampsia); SMAD4 (osteogenesis) |
[35,36,38,39,40,41] | |
| LOX/TGF-β feedback loop | LOX-modulated TGF-β1 regulating myofiber and muscle ECM balance and in inflammatory fibrotic stage (pulmonary fibrosis) | [43,44] | |
| Direct interaction: LOX-induced oxidative changes altered TGF-β receptor biding | Diminished TGF-β1 induced SMAD3 activation in a cross-talk with PI3K and AKT | [45] | |
| Integrins | LOX-stabilized ECM-mediated regulation | TGF-β pathway activation and a positive feedback for LOX expression | [49,50] |
| Stromal stiffness promoted LOX | Activation of integrin β1/GSK-3β/β-catenin (hepatocellular carcinoma) or Rho-Rho kinase myosin light chain axis (osteoarthritis) |
[51,53] | |
| ECM stiffness-driven inflammation, elevated LOX | Involving Rho activator GEF-H1 (lung endothelia) | [52] | |
| Injury-driven stromal alterations | TGF-β and LOX-dependent activation of integrin β1/pFAK/pAKT (epidermolysis bullosa subtype) or PI3K/AKT (angiogenesis) | [54,55] | |
| LOX promoted macrophage infiltration | Integrin β1/PYK2 activation via SRC/AKT/YAP1 (macrophages, glioblastoma); | [58] |
Ang II: type 2 angiotensin; EGFR: epidermal growth factor receptor LOX: lysyl oxidase; PDGF: platelet derived growth factor; VEGF: vascular endothelial growth factor; TGF-β: transforming growth factor beta; ADAM17: ADAM metallopeptidase domain 17; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; ERK: extracellular signal-regulated kinase; MEK: mitogen-activated protein kinase kinase/extracellular signal regulated kinase; SAPK: stress activated protein kinase; JNK: Jun N-terminal kinase; p38MAPK: P38 mitogen-activated protein kinase; HTRA1; M: HtrA serine peptidase 1; ATN2: atrophin 2; SHP2: SH2 domain protein tyrosine phosphatase, NF-κB: nuclear factor kappa B; HIF: hypoxia-inducible factor; ECM: extracellular matrix; COL1: type I collagen; AP-1: activator protein-1; GSK3: glycogen synthase kinase 3; GEF: guanine nucleotide exchange factor; FAK: focal adhesion kinase:; PYK2: proline-rich tyrosine kinase 2; YAP: yes-associated protein.