PICK1通过促进TGF-βⅠ型受体降解来抑制其信号转导
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摘要
转化生长因子β(transformation growth factor-beta, TGF-β)是一类结构上相关的细胞因子大家族，包括TGF-β、Activin、Nodal、骨形成蛋白(bone morphogenicproteins, BMPs)和Myostatin等。TGF-β在早期胚胎发育和组织稳态的维持过程中起着非常重要的作用。其信号转导起始于TGF-β配体与细胞膜表面I型和II型受体的结合，然后位于I型受体胞内段的丝氨酸/苏氨酸激酶区域可以进一步磷酸化Smad蛋白，使其在核内聚集并调控下游靶基因的表达。在不同微环境中，TGF-β信号强度受到严格的调控，而信号转导的失调与包括肿瘤和组织纤维化在内的多种疾病的发生有关。
PICK1(Protein that interacts with C kinase1)蛋白在神经系统中的研究较为深入，其经典功能是调控突触中AMPA受体的内吞和运输。PICK1蛋白在包括心脏，肺，肝和肾脏在内的多种器官中存在广泛的表达，但其在神经系统之外的功能还未被很好的描述，在信号转导及相关疾病发生中的潜在作用也尚未可知。
本论文发现，过量表达PICK1蛋白能够在多种细胞内广泛的抑制TGF-β信号转导。敲除Pick1基因能够有效的延长TGF-β I型受体（TβRI）的半衰期，并促进小鼠胚胎成纤维细胞对TGF-β刺激的响应。生物化学研究结果显示，PICK1蛋白是通过促进TβRI经蛋白酶体和溶酶体的降解来抑制TGF-β信号转导的。PICK1可通过其PDZ结构域直接结合TβRI的C末端，并作为脚手架蛋白加强TβRI和窖蛋白（caveolin-1）的相互作用，从而加强TβRI的脂筏/胞膜窖定位。我们进一步发现PICK1能够促进TβRI经窖蛋白介导的方式内吞，增加受体的泛素化及后续降解，从而抑制TGF-β信号转导。最后，我们在人类乳腺癌样本中观察到PICK1的蛋白表达水平与TβRI的蛋白水平及Smad2的磷酸化水平呈显著的负相关，提示PICK1可能通过抑制TGF-β信号影响乳腺癌的发展进程。这些结果显示，PICK1蛋白可作为TGF-β信号转导的重要负调控因子在神经系统之外发挥功能。我们的研究不但建立起PICK1蛋白与TGF-β信号通路的联系，还为深入理解PICK1的生理和病理功能，尤其是其对癌症发展的影响，提供了新的曙光。
Transformation growth factor-beta (TGF-β) belongs to a superfamily of structuralrelated cytokines, consisting of TGF-β, Activin, Nodal, BMPs (bone morphogenicproteins), myostatin and others. TGF-β plays critical roles in early embryonicdevelopment and tissue homeostasis. The signal transduction is initiated via the ligandbinding to two cell surface receptors (type I and type II receptors), and then the Ser/Thrkinase in the intracellular domain of the type I receptor phosphorylates the signalingmediators Smad proteins, leading to their nuclear accumulation and their regulation oftarget gene expression. TGF-β signaling is precisely controlled spatiotemporally, and itsderegulation has been associated with development of human diseases including cancerand tissue fibrosis.
PICK1(Protein that interacts with C kinase1) has been well studied in neuralsystem. Its classic function is controlling the endocytosis and trafficking ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in neuralsynapses. PICK1has ubiquitous expression in many organs including heart, lung, liverand kidney. The non-neural functions of PICK1are less addressed, and its potentialeffects on signal transduction and related diseases remain unclear.
Here we find that overexpression of PICK1inhibits TGF-β signaling transductionin various cell lines. Knockout of Pick1efficiently prolongs the halflife of TGF-β type Ireceptor (TβRI) and promotes the response of mouse embryonic fibroblast to TGF-βtreatment. Biochemical analyses reveal that PICK1antagonizes TGF-β signaling bytargeting TGF-β type I receptor (TβRI) for proteasome-mediated andlysosome-mediated degradation. PICK1can directly interact with the C-terminus ofTβRI via its PDZ domain and act as a scaffold protein to promote the interactionbetween TβRI and caveolin-1, leading to enhanced lipid raft/caveolae localization ofTβRI. Therefore, PICK1increases caveolin-1-mediated endocytosis, ubiquitination anddegradation of TβRI. Finally, a negative correlation between PICK1expression andTβRI or phospho-Smad2levels is observed in human breast tumors, indicating thatPICK1may participate in breast cancer development through inhibition of TGF-βsignaling. Our findings reveal a novel function of PICK1as an important negativeregulator of TGF-β signaling. Not only does this study reveal the relationship between PICK1and TGF-β signal transduction, but also it provides new insight intophysiological and pathological functions of PICK1, especially its effects on tumordevelopment.
PICK1(Protein that interacts with C kinase1)蛋白在神经系统中的研究较为深入，其经典功能是调控突触中AMPA受体的内吞和运输。PICK1蛋白在包括心脏，肺，肝和肾脏在内的多种器官中存在广泛的表达，但其在神经系统之外的功能还未被很好的描述，在信号转导及相关疾病发生中的潜在作用也尚未可知。
本论文发现，过量表达PICK1蛋白能够在多种细胞内广泛的抑制TGF-β信号转导。敲除Pick1基因能够有效的延长TGF-β I型受体（TβRI）的半衰期，并促进小鼠胚胎成纤维细胞对TGF-β刺激的响应。生物化学研究结果显示，PICK1蛋白是通过促进TβRI经蛋白酶体和溶酶体的降解来抑制TGF-β信号转导的。PICK1可通过其PDZ结构域直接结合TβRI的C末端，并作为脚手架蛋白加强TβRI和窖蛋白（caveolin-1）的相互作用，从而加强TβRI的脂筏/胞膜窖定位。我们进一步发现PICK1能够促进TβRI经窖蛋白介导的方式内吞，增加受体的泛素化及后续降解，从而抑制TGF-β信号转导。最后，我们在人类乳腺癌样本中观察到PICK1的蛋白表达水平与TβRI的蛋白水平及Smad2的磷酸化水平呈显著的负相关，提示PICK1可能通过抑制TGF-β信号影响乳腺癌的发展进程。这些结果显示，PICK1蛋白可作为TGF-β信号转导的重要负调控因子在神经系统之外发挥功能。我们的研究不但建立起PICK1蛋白与TGF-β信号通路的联系，还为深入理解PICK1的生理和病理功能，尤其是其对癌症发展的影响，提供了新的曙光。
Transformation growth factor-beta (TGF-β) belongs to a superfamily of structuralrelated cytokines, consisting of TGF-β, Activin, Nodal, BMPs (bone morphogenicproteins), myostatin and others. TGF-β plays critical roles in early embryonicdevelopment and tissue homeostasis. The signal transduction is initiated via the ligandbinding to two cell surface receptors (type I and type II receptors), and then the Ser/Thrkinase in the intracellular domain of the type I receptor phosphorylates the signalingmediators Smad proteins, leading to their nuclear accumulation and their regulation oftarget gene expression. TGF-β signaling is precisely controlled spatiotemporally, and itsderegulation has been associated with development of human diseases including cancerand tissue fibrosis.
PICK1(Protein that interacts with C kinase1) has been well studied in neuralsystem. Its classic function is controlling the endocytosis and trafficking ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in neuralsynapses. PICK1has ubiquitous expression in many organs including heart, lung, liverand kidney. The non-neural functions of PICK1are less addressed, and its potentialeffects on signal transduction and related diseases remain unclear.
Here we find that overexpression of PICK1inhibits TGF-β signaling transductionin various cell lines. Knockout of Pick1efficiently prolongs the halflife of TGF-β type Ireceptor (TβRI) and promotes the response of mouse embryonic fibroblast to TGF-βtreatment. Biochemical analyses reveal that PICK1antagonizes TGF-β signaling bytargeting TGF-β type I receptor (TβRI) for proteasome-mediated andlysosome-mediated degradation. PICK1can directly interact with the C-terminus ofTβRI via its PDZ domain and act as a scaffold protein to promote the interactionbetween TβRI and caveolin-1, leading to enhanced lipid raft/caveolae localization ofTβRI. Therefore, PICK1increases caveolin-1-mediated endocytosis, ubiquitination anddegradation of TβRI. Finally, a negative correlation between PICK1expression andTβRI or phospho-Smad2levels is observed in human breast tumors, indicating thatPICK1may participate in breast cancer development through inhibition of TGF-βsignaling. Our findings reveal a novel function of PICK1as an important negativeregulator of TGF-β signaling. Not only does this study reveal the relationship between PICK1and TGF-β signal transduction, but also it provides new insight intophysiological and pathological functions of PICK1, especially its effects on tumordevelopment.
引文
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