【摘 要】
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Transforming growth factor β(TGF-β)is a multifunctional polypeptide that plays critical roles in regulating a broad range of cellular functions and physiological processes.TGF-β signalling dysfunction contributes to many disorders,such as cardiovascular d
【机 构】
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Department of Cardiology and Institute of Vascular Medicine,Peking University Third Hospital;Key Lab
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Transforming growth factor β(TGF-β)is a multifunctional polypeptide that plays critical roles in regulating a broad range of cellular functions and physiological processes.TGF-β signalling dysfunction contributes to many disorders,such as cardiovascular diseases,cancer and immunological diseases.The homoeostasis of negative feedback regulation is critical for signal robustness,duration and specificity,which precisely control physiological and pathophysiological processes.However,the underlying mechanism by which the negative regulation of TGF-β signalling is integrated and coordinated is still unclear.Here,we reveal that haematopoietic progenitor kinase-interacting protein of 55 kDa(HIP-55)was upregulated upon TGF-β stimulation,while the loss of HIP-55 caused TGF-β signalling overactivation and the abnormal accumulation of downstream extracellular matrix(ECM)genes.HIP-55 interacts with Smad7 and competes with Smad7/Axin complex formation to inhibit the Axin-mediated degradation of Smad7.HIP-55 further couples Smad7 to TβRⅠ but not TβRⅡ,driving TβRⅠ degradation.Altogether,our findings demonstrate a new mechanism by which the effector and negative feedback functions of HIP-55 are coupled and may provide novel strategies for the treatment of TGF-βsignalling-related human diseases.
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