How signaling pathways link extracellular mechano‐environment to proline biosynthesis: A hypothesis

Abstract

We propose a signaling pathway in which cell-extracellular matrix (ECM) adhesion components PINCH-1 and kindlin-2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH-1 expression via integrin signaling, which suppresses dynamin-related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin-2 translocation into mitochondria and interaction with Δ 1 -pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1). Kindlin-2 interaction with PYCR1 protects the latter from proteolytic degradation, leading to elevated PYCR1 level. Additionally, PINCH-1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. K E Y W O R D Scancer, collagen, extracellular mechano-environment, fibrosis, focal adhesion proteins, mitochondrial dynamics, proline biosynthesis OMM, outer mitochondrial membrane; P5C, Δ 1 -pyrroline-5-carboxylate; P5CS, Δ 1 -pyrroline-5-carboxylate synthase; PH, pleckstrin homology; PYCR, Δ 1 -pyrroline-5-carboxylate reductase; ROS, reactive oxygen species; TCA, tricarboxylic acid; TGF, transforming growth factor as an electron donor. Proline biosynthesis are influenced by both the availability of the substrate (i.e. P5C) and the expression levels and activities of the enzyme (i.e. PYCR). Three isoforms of PYCR, namely PYCR1, 2, and L, have been identified in mammals. [1,4] PYCR1 and 2 share a high level (approximately 84%) of similarity in amino acid sequence, whereas the similarity in amino acid sequence between PYCRL and PYCR1/2 is considerably lower (approximately 45%).All three PYCRs are encoded by genes (i.e. PYCR1, 2, and L) in the nuclei. However, after PYCR1 and 2 proteins are synthesized, they are transported from the cytosol into mitochondria where they catalyze the final step in proline biosynthesis (i.e. conversion of P5C to proline).

Current Advances in 3D Bioprinting for Cancer Modeling and Personalized Medicine

“…The main glucose metabolism changes induced by extracellular stiffness are represented by changes in glucose uptake by GLUT transporters, regulation of glycolysis, regulation of the pentose phosphate pathway through the PI3K-AKT pathway, and glycogen metabolism through AMPK [ 189 , 190 , 191 , 192 , 193 ]. Amino acid metabolism is also affected by extracellular stiffness, in particular the modulation of proline synthesis, which is mediated by Kindlin-2 [ 194 , 195 ]. YAP/TAZ, through mTORC1, will also potentiate amino acid uptake, and activation of the PI3K/AKT pathway appears to upregulate SLC6A19 protein, a promoter of amino acid uptake [ 196 , 197 ].…”

Current Advances in 3D Bioprinting for Cancer Modeling and Personalized Medicine

“…Main glucose metabolism changes induced by extracellular stiffness are represented by changes in glucose uptake by GLUT transporters, regulation of glycolysis, regulation of the pentose phosphate pathway through the PI3K-AKT pathway, and glycogen metabolism through AMPK [174][175][176][177][178]. Amino acid metabolism is also affected by extracellular stiffness, in particular, the modulation of proline synthesis, which is mediated by Kindlin-2 [179,180]. YAP/TAZ, through mTORC1, will also potentiate amino acid uptake, and activation of the PI3K/AKT pathway appears to upregulate SLC6A19 protein, promoter of amino acid uptake [181,182].…”