Trk (NTRK) 受体和 NTRK 基因融合是多种肿瘤的致癌驱动因素。尽管 Trk 受体通常在细胞表面被激活，但组成型活性 Trk 和多种细胞内 NTRK 融合癌基因的信号传导却很少被研究。在这里，我们证明细胞内的高丰度足以实现 TrkB 激酶结构域的不依赖于神经营养蛋白的组成型激活。在 HEK293 细胞中，组成型活性 TrkB 激酶和细胞内 NTRK2 融合癌基因 (SQSTM1-NTRK2) 减少了肌动蛋白丝状伪足动力学，磷酸化了 FAK，并改变了细胞形态。非典型细胞反应可以用细胞内激酶结构域来模拟，该结构域不会激活 Trk 相关的 MAPK/ERK 通路。在胶质母细胞瘤样 U87MG 细胞中，TrkB 或 SQSTM1-NTRK2 的表达降低了细胞运动性并导致转录组发生剧烈变化。临床批准的 Trk 抑制剂或激酶结构域中的 Y705 突变可阻断细胞效应和转录组变化。 TrkA 和 TrkC 也出现非典型信号传导。此外，在巢蛋白阳性胶质母细胞瘤的活检中发现了非典型 pTrk 激酶的标志。因此，我们建议对 NTRK 相关（脑）肿瘤活检进行类似蛋白质印迹的免疫分析筛查，以识别具有非典型 panTrk 或磷酸化 Trk 信号的患者。此类患者可能适合接受 NTRK 抑制剂（例如 Larotretinhib 或 Entretinhib）治疗。© 2024。作者。

Trk (NTRK) receptor and NTRK gene fusions are oncogenic drivers of a wide variety of tumors. Although Trk receptors are typically activated at the cell surface, signaling of constitutive active Trk and diverse intracellular NTRK fusion oncogenes is barely investigated. Here, we show that a high intracellular abundance is sufficient for neurotrophin-independent, constitutive activation of TrkB kinase domains. In HEK293 cells, constitutive active TrkB kinase and an intracellular NTRK2-fusion oncogene (SQSTM1-NTRK2) reduced actin filopodia dynamics, phosphorylated FAK, and altered the cell morphology. Atypical cellular responses could be mimicked with the intracellular kinase domain, which did not activate the Trk-associated MAPK/ERK pathway. In glioblastoma-like U87MG cells, expression of TrkB or SQSTM1-NTRK2 reduced cell motility and caused drastic changes in the transcriptome. Clinically approved Trk inhibitors or mutating Y705 in the kinase domain, blocked the cellular effects and transcriptome changes. Atypical signaling was also seen for TrkA and TrkC. Moreover, hallmarks of atypical pTrk kinase were found in biopsies of Nestin-positive glioblastoma. Therefore, we suggest Western blot-like immunoassay screening of NTRK-related (brain) tumor biopsies to identify patients with atypical panTrk or phosphoTrk signals. Such patients could be candidates for treatment with NTRK inhibitors such as Larotrectinhib or Entrectinhib.© 2024. The Author(s).