Panoply™ Human NTRK1 Knockdown Stable Cell Line

Multiple cancer signaling networks are regulated through reciprocal interactions with the Hippo tumor suppressor pathway via the transcriptional cofactor Yes-associated protein (YAP). However, how YAP is regulated by these inter-pathway interactions during tumorigenesis remains unclear. Here, researchers performed a targeted kinase inhibitor screen in human cancer cells to identify novel Hippo pathway regulators. Notably, they identified the nerve growth factor (NGF) receptor tyrosine kinase (NTRK1), a molecule previously not known to be associated with the Hippo signaling pathway. Inhibition of NTRK1 reduced YAP-driven transcription, cancer cell proliferation, and migration. Furthermore, using complementary functional genomics approaches and a mouse xenograft model, the researchers demonstrated that NTRK1 regulates YAP oncogenic activity in vivo. Mechanistically, inhibition of NTRK1 induced phosphorylation of large suppressor kinase 1 (LATS1) and controlled the subcellular localization of YAP. Taken together, these results provide strong evidence for an interaction between the NGF-NTRK1 pathway and the Hippo cancer pathway.

To determine whether inhibiting NTRK1 would affect xenograft tumor growth, researchers constructed NTRK1 knockdown PANC1 and MDA-MB231 cells. As expected, levels of p-LATS1 and p-YAP were increased in NTRK1 knockdown cells (Figure 1a). Similarly, when these cells were treated with NGF, the previously observed decrease in p-YAP and p-LATS1 protein levels disappeared, further confirming the crucial role of NTRK1 in mediating NGF action through the Hippo pathway (Figure 1b). Finally, NTRK1 knockdown PANC1 and MDA-MB231 cells and control cells were subcutaneously injected into SCID mice, and tumor growth was monitored. Compared to mice injected with control cells, tumor growth was inhibited in mice injected with NTRK1 knockdown cells (Figure 1c). Furthermore, Western blot analysis confirmed that YAP protein levels were significantly reduced in NTRK1 knockdown tumors (Figure 1d).

Figure 1. Knockdown of NTRK1 suppresses tumour growth in vivo. (Yang X, et al., 2019)