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ADAMTS9 Cleaves TMEM67, Disrupting Wnt and Cilia
- Researchers have discovered that the cleavage of TMEM67 by ADAMTS9 plays a crucial role in regulating both Wnt signaling and ciliogenesis, shedding light on the complexities of cellular processes in embryonic development and ciliopathies.
- TMEM67 mutations are associated with Meckel-Gruber syndrome, a congenital disorder, with TMEM67 encoding the meckelin protein localized to primary cilia, essential for developmental signaling pathways.
- ADAMTS9, known for ECM remodeling, selectively cleaves TMEM67, separating Wnt signaling from ciliogenesis, acting as a molecular switch in tissue morphogenesis and embryonic patterning.
- This cleavage disrupts TMEM67's ability to mediate Wnt signaling while preserving ciliogenesis, highlighting a precise regulatory mechanism allowing cells to adjust developmental signals independently.
- The study's use of biochemical assays and genetic models validated the cleavage's physiological effects on signaling outputs, opening avenues for exploring related proteases and substrates in cilia-associated signaling.
- Potential therapeutic implications arise from targeting ADAMTS9 to modulate Wnt signals without affecting ciliary structure, offering new treatment avenues for disorders involving aberrant Wnt signaling and ciliogenesis defects.
- The study proposes that differential TMEM67 proteolysis serves as a temporal regulatory mechanism, permitting cells to dynamically respond to environmental and developmental cues by toggling between Wnt signaling and ciliary functions.
- The research delves into evolutionary perspectives, suggesting that the proteolytic regulation of TMEM67 and ADAMTS9 has evolved to refine signaling specificity, emphasizing the separation of cilia formation from signaling control.
- By altering TMEM67-associated protein complexes within the ciliary membrane, the cleavage event may impact the assembly and function of ciliary components, influencing the distribution of signaling molecules during development.
- The study's interdisciplinary approach underscores the intricate relationship between proteolysis and signal transduction, offering insights into ciliary disorders and paving the way for innovative therapeutic strategies targeting ciliopathies and developmental diseases.
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