Lysyl oxidase propeptide promotes adipogenesis through inhibition of FGF-2 signaling

Abstract

Lysyl oxidase (LOX) catalyzes the oxidative deamination of lysine residues in collagen and elastin, key components of connective tissue. LOX is synthesized as an inactive 50 kD pre-proenzyme, and secreted to the extracellular matrix where it is cleaved into an active 32 kD LOX, and an 18kD free propeptide (LOX-PP), purportedly an inhibitor of fibroblast growth factor-2 (FGF-2) signaling. Given that adipocytes are distributed inside the connective tissue, it is likely that LOX-PP has an important regulatory role in adipogenesis, which has not been studied. Using NIH 3T3-L1 cells, we observed that FGF-2 inhibited adipogenesis, and LOX-PP promoted adipogenesis of 3T3-L1 cells in the presence of FGF-2; the expression of peroxisome proliferator-activated receptor (PPAR) g and CCAAT-enhancer binding protein (C/EBP) a, two markers of adipogenesis, were enhanced in the presence of LOX-PP. We further observed that LOX-PP down-regulated AKT and ERK1/2, two proliferative signaling proteins down-stream of FGF-2 signaling. Similarly, inhibition of FGF-2 receptor signaling by canofin, a competitive inhibitor of FGF-2 receptor, promoted adipogenesis albeit less effective compared to LOX-PP. To further explore whether LOX-PP promoted adipogenesis through inhibition of FGF-2 signaling, site directed mutagenesis of LOX-PP, resulting in an Arg158 to Gln158 mutation which abolishes the inhibitory activity of LOX-PP to FGF-2 receptor, attenuated the adipogenic promoting properties of LOX-PP. In summary, for the first time, our data show that LOX-PP enhances adipogenesis at least partially through inhibition of FGF-2 receptor signaling. Our data suggest that LOX-PP may serve as a bona fide therapeutic target for regulating adipogenesis and adipose tissue development.

Dynamic changes in copper homeostasis and post-transcriptional regulation ofAtp7aduring myogenic differentiation

“…We hypothesized that myogenesis requires mobilization of Cu to the trans -Golgi network (TGN) as many secreted cuproenzymes are critical for differentiation of other progenitor cells. 47 , 48 Therefore, we analysed expression of ATP7A, the Cu-ATPase that transports Cu into the TGN. We quantified Atp7a mRNA levels using qRT-PCR and detected increased steady-state levels of Atp7a mRNA that peak at 24 h of differentiation ( Fig.…”

Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners

“…The cleavage sites of LOX-PP by MMP-2 (Asn150-Leu151 in rat, and Asn156-Leu157 in human) and BMP-1 24 (Gly168-Asp169) and the arginine residue R158, crucial for the adipogenic effect of LOX-PP, are not located in the HP-binding region. This residue plays an important role in LOX-PP functions because its mutation in glutamine inhibits the adipogenic effect of LOX-PP 14 and impairs the ability of LOX-PP to inhibit the invasive phenotype and tumor formation of breast cancer cells 42 . In contrast to the above residues, the cleavage site of MMP-10 (Ser56-Leu57) 25 , and P111 and R116, which are required for LOX-PP binding to CIN85 19 , are in the HP-binding region.…”

“…It induces phenotypic reversion of ras-transformed cells 11 , and inhibits cell signaling and proliferation of smooth muscle cells and osteoblasts 12 , 13 . The inhibition of FGF-2 signaling by LOX-PP in NIH 3T3-L1 cells contributes to its proadipogenic effect 14 . LOX-PP inhibits the growth of prostate cancer cells by interacting with DNA repair proteins 15 .…”

Lysyl Oxidase Down-Regulates The Osteoblastic Potential of BMP9 Through Inhibiting HIF-1α/Wnt/β-Catenin Axis in Mesenchymal Stem Cells

“…Lox, also named as protein lysine 6-oxidase, can converse lysine or lysine residue to aldehyde and promote the physicological cross-link process of the matrix protein, which is very important for the mature of connective tissue (10,11). It was reported that Lox plays an important role in the lineage commitment of adipocyte during the development (34). Besides, the abnormal level of Lox is associated with the biological behavior of cancer cells, such as metastasis (14).…”

“…It was reported that Lox can promote adipogenesis through inhibiting the signal of FGF-2. Lox promoted the adipogenic transcriptional factors, such as PPARγ and CCAAT enhancer binding protein (C/EBP) α in 3T3-L1 cells (34). Usually, the commitment of progenitor cells between osteogenesis and adipogenesis is mutual exclusive.…”