血小板源性生长因子受体α（platelet-derived growth factor receptor alpha，PDGFRA）是一种受体酪氨酸激酶，在胚胎发育、细胞增殖、迁移和分化过程中发挥关键作用。其异常激活与多种恶性肿瘤、纤维化及免疫疾病密切相关。本文系统综述了PDGFRA的结构特征、信号机制、在多种疾病中的作用及靶向药物的研究进展，为进一步的基础研究和精准治疗提供参考。
1. PDGFR的研究背景
2. PDGFRA的结构与功能基础
3. PDGFRA的信号通路
4. PDGFRA与疾病
5. PDGFRA靶向药物研究进展
6. PDGFRA研究工具
1. PDGFR的研究背景
血小板源性生长因子受体（PDGFR）属于受体酪氨酸激酶（RTK）家族，包括PDGFRA和PDGFRB两个亚型 [1,2]。其中，PDGFRA主要介导PDGF-AA、PDGF-AB及PDGF-CC等配体信号 [3]。在胚胎发育过程中，PDGFRA广泛表达于间充质细胞、成纤维细胞及平滑肌祖细胞中，对细胞迁移、组织重塑及血管生成具有重要作用 [4]。
在病理状态下，PDGFRA信号异常被认为是多种疾病的关键致病机制，包括肿瘤、纤维化、动脉粥样硬化及神经系统疾病 [5,6]。特别是在胃肠道间质瘤（GIST）中，PDGFRA基因突变可导致受体构象改变和持续激活，是继KIT突变后的另一主要驱动因素 [7]。
2. PDGFRA的结构与功能基础
2.1 PDGFRA的结构特征
PDGFRA基因位于4q12染色体，编码约1089个氨基酸的跨膜糖蛋白，包含五个免疫球蛋白样胞外结构域、单一跨膜结构域以及胞内酪氨酸激酶结构域 [11]。其中，第3、第4结构域为配体结合区，第5结构域参与受体二聚化 [12]。受体活化后，其胞内酪氨酸残基被自磷酸化，为下游信号通路提供结合位点 [13]。
PDGFRA与PDGFRB结构高度同源，但在配体特异性和信号转导上存在差异。PDGFRA主要响应PDGF-AA、PDGF-AB、PDGF-CC，而PDGFRB则对PDGF-BB及PDGF-DD更为敏感 [14]。
此外，PDGFRA还与其他受体如FGFR、EGFR存在交叉磷酸化，形成复杂的信号调控网络 [15]。
2.2 PDGFRA的配体与激活机制
PDGF家族由四种多肽链（A、B、C、D）组成，通过二聚化形成五种异/同源性配体：PDGF-AA、PDGF-BB、PDGF-AB、PDGF-CC、PDGF-DD [16]。这些配体与PDGFR亚型结合后诱导受体二聚化及自磷酸化，激活下游信号级联反应。
PDGF-AA主要结合PDGFRA同源二聚体（αα），而PDGF-BB能结合αα、ββ及αβ复合体 [17]。PDGF-CC在生理状态下需经蛋白酶裂解活化，其与PDGFRA结合后可促进细胞迁移与血管生成 [18]。
受体激活后，PDGFRA胞内多个酪氨酸残基（如Y572、Y742、Y988、Y1018）被磷酸化，分别与PI3K、PLCγ、Src及Shp2等分子结合，触发多条信号通路 [19,20]。
2.3 PDGFRA的生理功能
PDGFRA在组织发育与维持中发挥重要作用。胚胎期其在神经嵴、心脏、肺及肾脏发育中均不可或缺 [21]。缺失PDGFRA的小鼠表现出严重的发育缺陷，包括神经管畸形和血管生成障碍 [22]。在成人组织中，PDGFRA调控成纤维细胞、平滑肌细胞及肝星状细胞等的增殖与迁移 [23]。此外，其参与创伤修复及细胞外基质沉积 [24]。过度激活的PDGFRA信号常导致细胞过度增生与纤维化，是多种慢性疾病的重要病理基础 [25]。
3. PDGFRA的信号通路
PDGFRA激活后，可通过多条经典信号通路调控细胞增殖、分化、迁移与生存。主要包括PI3K/Akt、Ras/MAPK、JAK/STAT及PLCγ等通路。
3.1 PI3K/Akt通路
PI3K/Akt通路是PDGFRA介导的主要生存信号之一 [26]。受体激活后，PI3K结合磷酸化的酪氨酸残基（Y742）并被活化，随后催化PIP2转化为PIP3，招募Akt至质膜并被PDK1磷酸化 [27]。激活的Akt促进mTOR、GSK3β及BAD等下游分子磷酸化，从而增强细胞存活和代谢活性 [28]。在肿瘤细胞中，PI3K/Akt信号上调可抑制细胞凋亡并增强抗药性 [29]。此外，PDGFRA-PI3K/Akt信号还参与纤维母细胞向肌成纤维细胞分化，是纤维化形成的关键环节 [30]。
3.2 Ras/MAPK通路
Ras/MAPK通路主要介导细胞增殖与迁移信号。PDGFRA磷酸化的Y988和Y1018可招募Grb2-SOS复合物，激活Ras-GTP，并依次启动Raf-MEK-ERK级联反应 [31]。
ERK进入细胞核后促进转录因子AP-1、Elk-1及c-Fos的表达，调控细胞周期蛋白（Cyclin D1）转录，推动细胞从G1期进入S期 [32]。研究显示，PDGFRA的持续激活可导致MAPK通路过度活跃，引发细胞无限增殖，特别是在肿瘤和纤维化组织中 [33]。
3.3 JAK/STAT通路
JAK/STAT信号是PDGFRA调控免疫反应与细胞分化的重要途径。PDGFRA活化后可促进JAK1/2磷酸化，从而激活STAT1、STAT3及STAT5 [34]。激活的STAT蛋白进入细胞核，促进抗凋亡基因（如Bcl-2、Mcl-1）转录 [35]。在胶质瘤和白血病中，PDGFRA-JAK/STAT信号上调与肿瘤细胞存活密切相关 [36]。
同时，该通路还调控巨噬细胞极化及细胞因子分泌，在慢性炎症与免疫性疾病中具有重要作用 [37]。
3.4 PLCγ与Ca²⁺信号通路
PDGFRA还可激活磷脂酶Cγ（PLCγ）通路。受体的Y1021位点磷酸化后与PLCγ结合，使其催化PIP2分解为IP3和DAG [38]。IP3诱导内质网释放Ca²⁺，而DAG激活PKC，从而调控细胞迁移和收缩功能 [39]。这一通路在血管平滑肌细胞增殖与迁移中尤为重要，异常激活与动脉粥样硬化、血管重构密切相关 [40]。此外，Ca²⁺信号还能反馈调节PDGFRA磷酸化水平，形成动态平衡机制 [41]。
3.5 信号通路的交叉调控
PDGFRA介导的信号网络高度复杂，不同通路间存在交叉调节。例如PI3K/Akt可通过抑制Raf激活调控MAPK信号强度 [42]；ERK则能反馈调节PDGFRA的磷酸化，限制其过度活化 [43]。
此外，PDGFRA还可与TGF-β、EGFR及VEGFR等通路相互作用，形成多层级信号网络 [44]。在肿瘤微环境中，这些交叉调控加剧细胞生长失控与耐药性 [45]。
因此，理解PDGFRA相关通路间的动态互作对精准治疗具有重要意义。
4. PDGFRA与疾病
PDGFRA的异常激活与多种疾病密切相关，包括恶性肿瘤、纤维化疾病、心血管及神经系统疾病等。其作用机制主要涉及细胞信号持续激活、免疫微环境改变和细胞外基质重塑。
4.1 PDGFRA与肿瘤
4.1.1 胃肠道间质瘤（GIST）
GIST是PDGFRA研究最深入的肿瘤类型之一。约10–15%的GIST携带PDGFRA突变，其中最常见的是外显子18的D842V突变，导致受体持续激活并对伊马替尼耐药 [46]。阿伐普替尼（avapritinib）作为新型高选择性抑制剂，可有效靶向D842V突变，显著改善患者无进展生存期 [48]。
4.1.2 胶质瘤与脑肿瘤
PDGFRA在胶质瘤中高频扩增或过表达，特别是儿童高等级胶质瘤（HGG）[50]。PDGFRA信号可通过PI3K/Akt和STAT3通路促进神经胶质前体细胞无限增殖 [51]。
在动物模型中，PDGFRA的持续活化可独立驱动肿瘤形成，而联合p53缺失则显著增强恶性程度 [52]。
4.1.3 肺癌与其他实体瘤
PDGFRA在肺腺癌、结直肠癌、乳腺癌等多种实体瘤中亦有异常表达 [55]。其信号上调与肿瘤间质细胞激活、血管生成及转移相关 [56]。例如，在非小细胞肺癌中，肿瘤相关成纤维细胞（CAF）分泌PDGF-AA可激活PDGFRA促进肿瘤进展 [57]。抑制PDGFRA可降低肿瘤细胞侵袭性并增强免疫治疗反应 [58]。
4.2 纤维化相关疾病
PDGFRA信号在多种器官纤维化中被异常激活。其促进成纤维细胞增殖及细胞外基质沉积，是纤维化形成的关键驱动力。在肝纤维化中，PDGFRA通过Akt/mTOR通路促进肝星状细胞活化与胶原合成 [59]。抑制PDGFRA可显著减轻肝组织纤维化程度 [60]。在肺纤维化模型中，PDGFRA的上调导致成纤维细胞持续活化；Nintedanib等多靶点TKI通过抑制PDGFRA/FGFR/VEGFR信号改善疾病进程 [61]。
此外，在肾小球硬化及心肌纤维化中，PDGFRA信号促进肌成纤维细胞分化，增强ECM沉积，形成不可逆组织重塑 [62]。
4.3 心血管系统疾病
PDGFRA在血管发育及损伤修复中具有双重作用。适度激活可促进血管平滑肌增殖及再生，而持续过度激活则引起血管重构和粥样硬化 [47]。研究显示，PDGFRA信号通过PLCγ/Ca²⁺及ERK通路调节平滑肌细胞迁移 [49]；其在动脉损伤后的过度激活会导致新生内膜形成 [53]。抑制PDGFRA可减少血管平滑肌异常增生并改善再狭窄风险 [8]。因此，PDGFRA被认为是血管病干预的重要潜在靶点。
4.4 神经系统疾病
PDGFRA在神经系统发育与修复中同样重要。其在少突胶质前体细胞（OPC）中表达，对髓鞘形成和再生至关重要 [9]。在神经损伤或退行性疾病中，PDGFRA信号调控神经胶质细胞增殖与轴突再生 [10]。然而，过度激活的PDGFRA可能导致异常胶质细胞增生，与神经胶质瘤形成相关 [54]。因此，维持PDGFRA信号平衡对神经稳态至关重要。
5. PDGFRA靶向药物研究进展
目前，针对PDGFRA靶点的药物研发呈现出多元化趋势，涵盖了小分子化药、单克隆抗体、CAR-T细胞疗法等多种类型。如下表所示，除已广泛批准用于治疗胃肠道间质瘤的瑞派替尼、阿伐替尼等多靶点药物外，更有众多候选药物处于不同研发阶段，其适应症已扩展至肺动脉高压、特发性肺纤维化、软组织肉瘤等多种疾病，展现了该靶点广阔的临床开发前景。
（数据截止到2025年11月10日，来源于synapse）
6. PDGFRA研究工具
PDGFRA作为重要的受体酪氨酸激酶，在多种生理与病理过程中发挥核心作用。其异常激活与肿瘤、纤维化、心血管及神经疾病密切相关。华美生物提供PDGFRA重组蛋白、抗体及ELISA试剂盒产品，助力您进行相关机制研究及靶向药物开发。
● PDGFRA重组蛋白
Recombinant Human Platelet-derived growth factor receptor alpha (PDGFRA), partial (Active); CSB-MP017712HU1
● PDGFRA抗体
PDGFRA (tovetumab) Recombinant Monoclonal Antibody; CSB-RA017712MA1HU
● PDGFRA ELISA试剂盒
Mouse Platelet-Derived Growth Factor Soluble Receptor α,PDGFsR-α ELISA kit; CSB-E04699m
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