{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlthough none of the provided abstracts directly study PPM1L, they collectively illustrate the crucial importance of negative regulation in the TGF‑β/Smad signaling pathways across multiple tissues. In these studies the inhibitory molecules—most notably Smad7 and its interacting partners such as Arkadia, Smurf1/2, and YAP65—are shown to temper TGF‑β–driven responses that otherwise promote fibrosis, inflammation, apoptosis, and abnormal cellular proliferation in organs like the liver, kidney, heart, pancreas, and even the skin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFor example, several reports demonstrate that robust up‐regulation of Smad7 in response to TGF‑β or BMP signals sets up a negative feedback loop capable of inhibiting downstream Smad2/3 phosphorylation. This in turn results in decreased transcription of fibrogenic and pro‑inflammatory mediators, thereby lessening progression of tissue fibrosis and ameliorating cellular apoptosis in experimental renal, cardiac, and pulmonary disease models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional work has detailed how modulators of TGF‑β signaling not only control Smad phosphorylation but also intersect with other pathways (including NF‑κB, MAPK, and Wnt) to coordinate diverse cellular outcomes such as differentiation, proliferation, and survival. Mechanisms such as Arkadia‑mediated polyubiquitination of Smad7 and enhanced recruitment of inhibitory partners contribute to curbing excessive signal propagation—a concept that suggests the existence of parallel phosphatase‐based controls. Although Smad7 is the primary inhibitory signal transducer discussed in these reports, PPM1L belongs to the PP2C family of serine/threonine phosphatases and is known from the wider literature to dephosphorylate key signaling intermediates; accordingly, its putative function would be to similarly deactivate components of the TGF‑β cascade, thereby providing an additional layer of control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several experimental settings—including models of fibrotic renal injury, post‑infarction cardiac remodeling, and aberrant epithelial repair—disruption or overexpression of inhibitory molecules has been linked with dramatic changes in extracellular matrix deposition, inflammatory cell recruitment, and cell survival. Such findings underscore the importance of a tightly regulated balance between phosphorylation and dephosphorylation events in TGF‑β signaling. In this context, even though PPM1L is not explicitly mentioned, by analogy its enzymatic dephosphorylation activity could serve to withdraw active phosphorylated Smads or even receptor complexes from the signaling pool, thereby attenuating the profibrotic and pro‑inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, insights from studies examining TGF‑β signaling in tumor suppression, immune regulation, and developmental processes (including skeletal myogenesis and intestinal homeostasis) reveal that modulation of signal duration and intensity is critical to prevent pathological outcomes. These investigations—although mainly focused on Smad7 and its partners—raise the possibility that phosphatases like PPM1L, as part of the broader negative regulatory machinery, could help restore cellular equilibrium by terminating signals once they have fulfilled their physiological roles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther evidence from studies focused on TGF‑β–driven pathological processes in diverse organs (from the kidney and liver to the gut and skeletal muscle) reinforces the concept that excessive or prolonged TGF‑β signaling leads to detrimental outcomes such as uncontrolled fibrosis and tumorigenesis. In these settings the inhibitory feedback provided by Smad7 is vital, and by extension, phosphatases like PPM1L are anticipated to contribute similarly by catalyzing dephosphorylation events that “switch off” active signaling. This termination of signaling is essential for restoring tissue homeostasis and preventing pathological remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, the collection of studies emphasizes that fine‑tuning the TGF‑β/Smad axis—via inhibitory components capable of blocking or reversing signal propagation—is critical for normal tissue repair, immunomodulation, and prevention of fibrosis and cancer. Although PPM1L is not directly evaluated in any of these abstracts, its membership in the PP2C phosphatase family implies a parallel role: dephosphorylating activated receptors or Smads to attenuate TGF‑β signaling. Such a function would be entirely consistent with the broader theme observed in these reports, and it supports the idea that PPM1L may serve as a natural “brake” on TGF‑β–mediated pathological processes, offering a potential therapeutic target in diseases marked by hyperactive TGF‑β signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Léon Kautz, Delphine Meynard, Annabelle Monnier, et al. 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