文章信息
- 非视紫质G蛋白偶联受体激酶对肿瘤的调控作用
- Regulation Role of Non-Rhodopsin G Protein-coupled Receptor Kinases on Tumor
- 肿瘤防治研究, 2019, 46(4): 367-370
- Cancer Research on Prevention and Treatment, 2019, 46(4): 367-370
- http://www.zlfzyj.com/CN/10.3971/j.issn.1000-8578.2019.18.1602
- 收稿日期: 2018-10-30
- 修回日期: 2018-12-22
外界环境刺激通过胞膜受体将信号从胞外转导到胞内。G蛋白偶联受体(G protein-coupled receptors, GPCRs)是迄今为止发现的最大的跨膜受体超家族,能接受多种细胞外信号刺激,是细胞正常生命活动的重要调节者和新药研发的重要靶点[1]。GPCRs的信号转导过程受G蛋白偶联受体激酶(G protein-coupled receptor kinase, GRKs)的调控。目前,在哺乳动物组织中共发现七个GRK家族成员并分为三个亚家族:(1)GRK1亚家族,特异性表达于视网膜,又称为视紫质激酶家族,通过磷酸化视紫红质受体介导光转导,包括GRK1和GRK7;(2)GRK2亚家族,或β-肾上腺素能受体激酶家族,包括GRK2和GRK3;(3)GRK4亚家族,包括GRK4、GRK5和GRK6。GRK4主要在脑、肾脏、睾丸和卵巢颗粒细胞中表达, GRK2、GRK3、GRK5和GRK6则可表达于全身组织,这5个GRKs分子又称为非视紫质GRKs[2]。非视紫质GRKs通过磷酸化活化状态的GPCRs或非GPCR磷酸化功能参与广泛的细胞生理和病理活动[2-3],其中一些信号通路与肿瘤的发生和演进密切相关,探讨其对肿瘤的调控作用,有助于深入理解肿瘤的发生与发展机制,为癌症诊断和治疗研究提供新思路。本文就近些年来非视紫质GRKs与肿瘤细胞增殖、生长及转移等信号调控研究进展作一综述。
1 GRKs的结构及功能GRKs属于丝/酪氨酸蛋白激酶家族,主要通过磷酸化不同的底物参与细胞信号通路的调控。
1.1 GRKs的结构迄今为止,在哺乳动物细胞中共发现7个GRK家族成员,分为GRK1(GRK1/7)、GRK2(GRK2/3)和GRK4(GRK4/5/6)三个亚家族。它们在结构上包含~185个氨基酸的氨基(N)端、~105~230个氨基酸的羧基(C)端和中央高度保守~270个氨基酸的激酶结构域[4]。其N-末端30个氨基酸在GRKs家族中高度保守,是识别活化的GPCR的关键位点;N端区包含G蛋白信号调节子(regulators of G protein signaling, RGS)同源序列结构域,调控GRKs与Gαq相互作用和自身同源二聚化[4-5]。C端与GRKs膜定位有关:GRK1和GRK7的C-末端含有法尼基化(farnesylation)和栊牛儿基化(geranylgeranylation)短序列,而GRK4和GRK6含多个能够被棕榈酰化的半胱氨酸残基,这些位点的酰化促使GRKs分子与质膜结合[4];GRK2和GRK3的C-末端结构域在受体激活后与游离的Gβγ亚基结合,进而与质膜磷脂相互作用[6];GRK5和GRK6的C-末端则存在一个由4个疏水性氨基酸残基为核心的质膜结合所必需的两性螺旋结构元基[4, 7]。
1.2 GRKs对GPCR的磷酸化GRKs是GPCR内化和磷酸化信号转导过程中重要的调节因子。GRKs通过磷酸化配体激活的GPCR,引发β-arrestin与受体结合,从而阻止G蛋白与GPCR偶联,快速“关闭”或“去敏(desensitization)”激动剂持续引发的信号转导,维持细胞自稳。首先,GPCR与β-arrestin的结合在空间上阻碍了受体与G蛋白相互作用。第二,促使GPCR内化、进入被膜小窝形成网格蛋白小体。内化的GPCR被脱磷酸化后,或迅速地返回质膜重复使用,或降解[2]。
1.3 GRKs磷酸化GPCR以外的重要生物学功能除了经典的磷酸化GPCR受体的作用,GRKs也通过磷酸化非GPCR底物影响信号转导。如GRK2和GRK5分别磷酸化IRS1和HDAC5[8-9]。GRK5可以与NF-κB结合进而稳定IκBα/NF-κB复合物[10],磷酸化p53进而促进后者降解[11],以及定位于细胞中心体进而参与中心体的微管成核和细胞周期的调控[12]。GRK6与GRK相互作用蛋白(GIT)1结合,激活RAC1信号通路、促进小鼠脾脏凋亡免疫细胞的清除[13]。另一方面,GRKs通过与PI3K、clathrin、GIT、caveolin、MEK、AKT和RKIP等信号分子结合,以非磷酸化的方式参与细胞活动。多个GRK分子可以与G蛋白的Gq和Gβγ亚单位、MAP激酶结合而调控相关信号通路的转导[3]。GRK4在GABAB受体去敏过程中无受体磷酸化,也不需要有催化活性的激酶[14]。这些研究提示,GRKs除了磷酸化GPCR、去敏GPCR信号通路以外,还以磷酸化非GPCR或通过非磷酸化作用参与信号转导调控。
2 非视紫质GRKs对细胞分化与增殖的调控GRK2和GRK6通过抑制IGF1R介导的ERK及AKT信号通路、以及多个趋化因子受体(CXCR)的信号转导,负调控细胞生长[15-16]。GRK4通过磷酸化多巴胺受体抑制人肾脏近曲小管细胞的增殖[17]。GRK5能够磷酸化核仁磷酸蛋白1,调控细胞核组装、中心体复制和细胞分裂等过程;而磷酸化的核仁磷酸蛋白1促进细胞的凋亡[18]。GRK5分子含有功能性核输出序列,降低GPCR活性或终止钙离子信号的转导可以改变GRK5的核穿梭机制,从而导致细胞转化[19-20]。GRK5通过磷酸化p53,促进G2期向M期过渡[11]。GRK2和GRK5分布于中心体,可能促进有丝分裂早期中心体的分离[21-22]。本研究小组最近报道,GRK4过表达显著抑制人胚肾HEK293细胞的增殖,细胞发生衰老表型样改变,伴随18个与细胞周期调控、DNA损伤等关联基因的mRNA水平显著异常[23]。
3 非视紫质GRKs与肿瘤 3.1 GRKs的表达调控mRNA芯片数据显示,在不同肿瘤中,GRKs表达水平不同。组学研究发现,GRK2/GRK6基因扩增或GRK3/GRK5基因突变与缺失见于多种类型的肿瘤[24-25]。另一方面,GRKs表达和功能受到转录后修饰和与其他蛋白如Caveolin 1相互作用等因素调控,从而导致蛋白活性、定位或稳定性的改变[26]。
3.2 GRK2Métayé等报道GRK2在分化型甲状腺癌组织中高表达,可能通过去敏促甲状腺激素受体(TSHR)信号抑制甲状腺癌细胞增殖[27]。在肝癌HepG2细胞中,GRK2抑制IGF1R信号通路,进而抑制肝癌细胞增殖和迁移,可能为治疗肝癌提供新的作用靶点[28]。另一方面,胰腺癌组织中GRK2水平高表达者预后差[29]。乳腺上皮细胞中EGF或者HER2受体等被活化,通过增强PI3K/AKT通路刺激GRK2的表达[30]。GRK2过表达促进HDAC6磷酸化和活化,导致脯氨酰异构酶Pin1的去乙酰化,后者是肿瘤进展的调控因子,促进乳腺癌的发生与发展。真核翻译起始因子3d(eIF3d)可以通过调控GRK2的稳定性,增强PI3K/AKT信号通路,从而促进胆囊癌细胞的增殖和迁移[31]。在慢性淋巴细胞白血病细胞信号调控研究中发现,Locostatin的作用机制可能包括抑制RKIP与GRK2的结合,导致GRK2介导的MAPK-ERK1/2和AKT表达下调[32]。
3.3 GRK3在三阴型乳腺癌MDA-MB 231细胞模型中,敲降GRK3导致CXCL12/CXCR4信号通路活性增强、促进肿瘤细胞迁移和裸鼠移植瘤转移,提示GRK3可能通过负调控CXCR4信号转导而抑制乳腺癌转移[33]。在前列腺癌细胞中,GRK3过表达引起雄激素剥夺疗法激活的cAMP反应元件结合,促进前列腺癌的发生与发展[34];在结肠癌细胞中,GRK3过表达可以增强细胞增殖、抑制细胞凋亡,其机制有待深入研究[35]。
另一方面,多组肝癌患者单因素分析研究显示,GRK3高表达的患者生存率显著升高,提示GRK3可能负性调控肝癌的发生与发展进程[36]。在胶质母细胞瘤的亚型中也发现了GRK3 mRNA水平的降低,其中EGFR激活导致GRK3表达下调,而GRK3降低促进CXCR4表达升高和肿瘤生长[37]。
3.4 GRK4GRK4可以激活乳腺癌细胞中β-arrestin介导的ERK1/2和JNK信号通路,促进癌变[38]。在大鼠甲状腺功能亢进结节模型中,即使没有促甲状腺素受体突变和G蛋白α亚基突变,GRK3和GRK4的表达上调[39]。在卵巢颗粒细胞肿瘤中,GRK4 α/β亚基表达下调,而γ/δ亚基表达升高,提示GRK4不同亚基的表达可能参与卵巢颗粒细胞肿瘤的病理过程[40]。
3.5 GRK5与GRK2相反,GRK5通过增强TSHR活性促进甲状腺癌细胞生长[27]。沉默GRK5基因,可以抑制前列腺癌PC3细胞增殖,诱导G2/M期阻滞[41]。GRK5的促瘤效应可能与它磷酸化p53蛋白、促进p53降解,进而抑制细胞凋亡的功能有关[11]。在结肠癌HCT116细胞中,肿瘤抑制因子TIG-1通过抑制β-catenin信号通路来抑制PGE2诱导的细胞增殖,这一过程由GRK5调控[42]。GRK5在非小细胞肺癌的多个细胞系中表达量显著升高,GRK5高表达的患者生存率低、预后差。而突变GRK5基因可以抑制非小细胞肺癌细胞的增殖,促进细胞凋亡,提示GRK5有可能成为治疗肺癌的新靶标[43]。
3.6 GRK6GRK6在肺癌、胶质母细胞瘤、成神经管细胞瘤等肿瘤的生长与转移过程中发挥重要作用[44-46]。GRK6高表达与甲状腺乳头状癌的肿瘤大小和分期成正比,并增加癌复发的机率,提示GRK6促进甲状腺乳头状癌的生长[47]。与GRK5比较,GRK6高表达能促进结肠癌的发生发展,降低患者5年生存率,但是机制仍不清楚[48]。在肝细胞癌中,下调GRK6可以抑制CD97分子的内化,刺激下游基质金属蛋白酶2/9的分泌,从而促进肝细胞癌的转移[49]。另一方面,GRK6启动子的异常甲基化导致其在下咽喉鳞状细胞癌中表达下调,促进癌症的发展[50]。
4 结语非视紫质激酶家族GRKs参与调控多种肿瘤的发生与发展,不同GRKs分子对肿瘤细胞的调控作用不同,或抑制、或促进肿瘤细胞增殖与生长。在不同的肿瘤环境中,GRKs的功能改变时常常伴有相关GPCRs、原癌基因等分子功能的相应改变,目前对这些效应的观察还很肤浅,其详细的分子机制有待进一步揭示。
作者贡献
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蒋晓山: 指导修改、审核
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