Abstract L-lactate is generally elevated in tumors and acts as a signaling molecule that promotes tumor progression. Here, we reveal that malic enzyme 1 (ME1) functions as a previously unrecognized sensor of L-lactate through direct binding at arginine 155 (R155), thereby potentiating malignancy. Mechanistically, L-lactate binding promotes the nuclear translocation of ME1, a process involving reduced acetylation at lysine 362 (K362) and facilitated by nuclear import of karyopherin-α 4 (KPNA4). Nuclear accumulation of ME1 enhances metastatic potential, which is correlated with increased interaction with hepatoma-derived growth factor (HDGF) and acquisition of an epithelial‒mesenchymal transition (EMT)-related phenotype. Under nutrient-deficient conditions, L-lactate promotes the assembly of a ME1-lactate dehydrogenase B (LDHB) complex, which enhances oxidative phosphorylation (OXPHOS) and increases ATP production, suggesting a metabolic adaptive mechanism that supports tumor cell survival. Notably, the ME1R155A mutation, which disrupts L-lactate binding, abolishes the protumorigenic effect of the L-lactate-ME1 axis on tumor progression in vivo. In conclusion, our findings identify ME1 as a direct sensor of L-lactate and support a model in which lactate-mediated signaling and metabolic adaptation converge on ME1 to regulate tumor cell plasticity in a context-dependent manner under heterogeneous metabolic conditions. These insights advance our understanding of the spatiotemporal control of metabolic adaptation in cancer and reveal a potential therapeutic target.
The insulin-like growth factor (IGF) signaling pathway plays a pivotal role in regulating a myriad of cellular and physiological processes, including cell proliferation, differentiation, and the maintenance of redox homeostasis. This review provides a comprehensive overview of the IGF/IGF receptor (IGFR) signaling axis, outlining its historical milestones and delineating its evolution from foundational discoveries to contemporary advancements. We elucidate the structural components of pathway, including ligands, receptors, and IGF-binding proteins, and discuss how multilevel regulation integrates upstream signals with downstream effectors such as the PI3K-AKT and MAPK/ERK pathways. Particular emphasis is placed on the crosstalk between IGF signaling and other pathways, including insulin, EGFR, PDGFR, VEGF, Wnt/β-catenin, JAK-STAT, and TGF-β/BMP in homeostasis and pathophysiological processes. We further discuss the role of IGF signaling in pathological process, highlighting insights from animal models and its implication in a wide range of human diseases, including cancer, cardiovascular diseases, neurodegenerative conditions, metabolic syndromes, skeletal abnormalities, and autoimmune and rare genetic disorders. Finally, we examine the therapeutic potential of targeting the IGF/IGFR axis, current clinical research advancements, FDA-approved pharmacological agents, and ongoing clinical trials. By incorporating historical insights with up-to-date scientific breakthroughs, our review underscores the need for systems-level and context-specific approaches to better understand IGF signaling dynamics, thus paving the way for the development of precision and personalized therapeutic strategies.
Parathyroid hormone receptor-1 (PTH1R) is a class B GPCR that regulates mineral ion homeostasis via parathyroid hormone (PTH) and skeletal development via parathyroid hormone-related peptide (PTHrP). While PTHrP signaling is thought to occur predominantly at the plasma membrane, PTH is considered to also signal from endosomes; however, the mechanisms that encode subcellular PTH1R actions, as well as the biological relevance of plasma membrane vs internalized PTH1R activation, remain unclear. Here, by examining the Eiken syndrome mutant R485X-PTH1R, in which C-tail truncation removes key βarrestin docking sites, we identified βarrestins as critical modulators of compartmentalized PTH1R signaling in response to endogenous ligands. Patients with Eiken syndrome display delayed bone mineralization, consistent with enhanced PTHrP actions, as well as hypocalcemia along with elevated PTH, which paradoxically indicates impaired PTH function. Mechanistic studies in cell-based assays and humanized R485X-PTH1R knock-in mice revealed that βarrestins dampen PTHrP-driven Gαs signaling at the plasma membrane but promote PTH-induced endosomal PTH1R signaling. βarrestins thus appear to impose bimodal, compartment-specific modulation of PTH1R signaling, thereby resolving the paradoxical Eiken phenotype. The findings support the notion that differences in subcellular PTH1R localization determine ligand-specific signaling outcomes in skeletal physiology and mineral ion homeostasis.
Aberrant repair/regeneration of alveolar epithelial stem cells is a key driver of pulmonary fibrosis (PF). While βPAK-interacting exchange factor (βPIX) is connected to stem cell signaling, its role in pulmonary fibrosis (PF) remains unknown. Here, we generated conditional βPIX knockout mice to investigate its contribution to PF pathogenesis. Selectively depleting βPIX in alveolar type 2 (AT2) cells led to progressive PF in mice, recapitulating the key features observed in human idiopathic pulmonary fibrosis (IPF), where AT2 cells exhibit significantly reduced βPIX levels. Single-nucleus RNA sequencing of the lungs of βPIX-deficient mice revealed the emergence of progenitor cells in a transitional stem cell state with senescent attributes, along with active, collagen-producing myofibroblasts. Mechanistically, the loss of βPIX impaired AT2 cell stemness by downregulating Wnt/β-catenin signaling. AT2 cells from IPF patients also presented reduced levels of β-catenin and Axin2, confirming the downregulation of Wnt/β-catenin signaling. Treatment with a glycogen synthase kinase-3β inhibitor reactivated Wnt/β-catenin signaling and attenuated fibrosis in βPIX-deficient mice. Our results establish a direct causal link between βPIX deficiency and PF, highlighting βPIX and its downstream pathway as promising therapeutic targets for this devastating disease.
