The multifunctional roles of metabolic enzymes allow for the integration of multiple signals to precisely transduce external stimuli into cell fate decisions. Elevation of 3-phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for de novo serine biosynthesis, is broadly associated with human cancer development; although how PHGDH activity is regulated and its implication in tumorigenesis remains unclear. Here we show that glucose restriction induces the phosphorylation of PHGDH by p38 at Ser371, which promotes the translocation of PHGDH from the cytosol into the nucleus. Concurrently, AMPK phosphorylates PHGDH-Ser55, selectively increasing PHGDH oxidation of malate into oxaloacetate, thus generating NADH. In the nucleus, the altered PHGDH activity restricts NAD⁺ level and compartmentally repressed NAD⁺-dependent PARP1 activity for poly(ADP-ribosyl)ation of c-Jun, thereby leading to impaired c-Jun transcriptional activity linked to cell growth inhibition. Physiologically, nuclear PHGDH sustains tumour growth under nutrient stress, and the levels of PHGDH-Ser371 and PHGDH-Ser55 phosphorylation correlate with p38 and AMPK activity, respectively, in clinical human pancreatic cancer specimens. These findings illustrate a previously unidentified nutrient-sensing mechanism with the critical involvement of a non-canonical metabolic effect of PHGDH and underscore the functional importance of alternative PHGDH activity in tumorigenesis.

代谢酶的多功能作用允许整合多个信号，以将外部刺激精确地转导到细胞命运决定中。3-磷酸​​甘油酸脱氢酶 (PHGDH) 的升高是丝氨酸从头生物合成的限速酶，与人类癌症的发展广泛相关；尽管如何调节 PHGDH 活性及其在肿瘤发生中的意义仍不清楚。在这里，我们显示葡萄糖限制通过 p38 在 Ser371 处诱导 PHGDH 的磷酸化，从而促进 PHGDH 从细胞质转移到细胞核中。同时，AMPK 磷酸化 PHGDH-Ser55，选择性地增加 PHGDH 将苹果酸氧化为草酰乙酸，从而产生 NADH。在细胞核中，改变的 PHGDH 活性限制了 NAD ⁺c-Jun 的多聚（ADP-核糖基）化的NAD ^{+依赖性 PARP1 活性受到区室抑制，从而导致与细胞生长抑制相关的 c-Jun 转录活性受损。}生理学上，核 PHGDH 在营养胁迫下维持肿瘤生长，临床人胰腺癌标本中 PHGDH-Ser371 和 PHGDH-Ser55 磷酸化水平分别与 p38 和 AMPK 活性相关。这些发现说明了一种以前未确定的营养感应机制，其中 PHGDH 的非典型代谢作用至关重要，并强调了替代 PHGDH 活性在肿瘤发生中的功能重要性。