Abstract
Proline metabolism is critical for cellular response to microenvironmental stress in living organisms across different kingdoms, ranging from bacteria, plants to animals. In bacteria and plants, proline is known to accrue in response to osmotic and other stresses. In higher organisms such as human, proline metabolism plays important roles in physiology as well as pathological processes including cancer. The importance of proline metabolism in physiology and diseases lies in the fact that the products of proline metabolism are intimately involved in essential cellular processes including protein synthesis, energy production and redox signaling. A surge of protein synthesis in fast proliferating cancer cells, for example, results in markedly increased demand for proline. Proline synthesis is frequently unable to meet the demand in fast proliferating cancer cells. The inadequacy of proline or “proline vulnerability” in cancer may provide an opportunity for therapeutic control of cancer progression. To this end, it is important to understand the signaling mechanism through which proline synthesis is regulated. In a recent study (Guo et al., Nat Commun 11(1):4913, doi: 10.1038/s41467-020-18753-6), we have identified PINCH-1, a component of cell-extracellular matrix (ECM) adhesions, as an important regulator of proline synthesis and cancer progression.
Highlights
The importance of kindlin-2 mitochondrial translocation and interaction with PYCR1 in regulation of proline synthesis and cancer progression begs the question of what signaling proteins regulate kindlin-2 mitochondrial translocation and interaction with PYCR1
How does PINCH-1 regulate proline synthesis? Proline is synthesized in cells through reduction of Δ1-pyrroline-5carboxylate (P5C) with NAD(P)H as an electron donor, a reaction catalyzed by pyrroline-5-carboxylate reductase (PYCR)
Our previous studies have found that a fraction of kindlin-2, an integrin-binding protein that is concentrated at cell-extracellular matrix (ECM) adhesions, is translocated into mitochondria where it directly interacts with PYCR1
Summary
The importance of kindlin-2 mitochondrial translocation and interaction with PYCR1 in regulation of proline synthesis and cancer progression begs the question of what signaling proteins regulate kindlin-2 mitochondrial translocation and interaction with PYCR1. Mitochondrial dynamics links PINCH-1 signaling to proline metabolic reprogramming and tumor growth A surge of protein synthesis in fast proliferating cancer cells, for example, results in markedly increased demand for proline.
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