Transforming Growth Factor (TGF)-β Promotes de Novo Serine Synthesis for Collagen Production

Abstract

TGF-β promotes excessive collagen deposition in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). The amino acid composition of collagen is unique due to its high (33%) glycine content. Here, we report that TGF-β induces expression of glycolytic genes and increases glycolytic flux. TGF-β also induces the expression of the enzymes of the de novo serine synthesis pathway (phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH)) and de novo glycine synthesis (serine hydroxymethyltransferase 2 (SHMT2)). Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for TGF-β-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF.

Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress

“…As reported by others (Nigdelioglu et al , ; Selvarajah et al , ), TGFβ‐stimulated cells displayed a higher glycolytic activity (Fig EV1D–F). We found that the increase in glucose uptake is an early event in response to TGFβ stimulation and plateaus after 24 h (Fig EV1G).…”

“…Glucose‐derived glycine has been shown to be incorporated into collagen I (Nigdelioglu et al , ), but whether fibroblasts use glutamine‐derived proline for the biosynthesis of collagen I is not known. To test this, we cultured NIH‐3T3 fibroblasts in the presence of unlabeled ([ 12 C]) or fully labeled ([U‐ 13 C]) glutamine and extracted cell‐derived ECM for proteomic analysis (Fig K).…”

“…Recent evidence indicates that activation of TGFβ signaling supports these processes at least in part by reprogramming cellular metabolism. For instance, TGFβ‐mediated activation and differentiation of fibroblasts into extracellular matrix (ECM)‐producing myofibroblasts are accompanied by an increase in glucose uptake, glycolytic metabolism, and activation of the serine/glycine biosynthetic pathway (Andrianifahanana et al , ; Nigdelioglu et al , ; Selvarajah et al , ). In addition, glutaminolysis is required for TGFβ‐induced collagen production (Bernard et al , ; Hamanaka et al , ).…”

TGF‐β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

“…TGF-b1 enhances glycolysis, amino acid uptake and lactate production in ras-and myctransformed cell cultures [13]. TGF-b1 contributes to the metabolic reprogramming of both cancer cells and tumor-associated stromal cells [14][15][16][17][18][19][20]. Neoplastic cells require higher glucose metabolism in order to satisfy the increased energetic and anabolic needs of the transformed state.…”

“…TGF-b1 secretion is enhanced in glioblastoma multiforme, [9,10], in which it acts as an oncogenic factor [11,12]. TGF-b1 contributes to the metabolic reprogramming of cancer cells and tumor-associated stromal cells [14][15][16][17][18][19][20]. TGF-b1 contributes to the metabolic reprogramming of cancer cells and tumor-associated stromal cells [14][15][16][17][18][19][20].…”