posted on 2023-06-08, 21:53authored byYichen Xu, Hua Zhang, Van Nguyen, Nikos Angelopoulos, Joao Nunes, Alistair Reid, Laki Buluwela, Luca Magnani, Justin Stebbing, Georgios GiamasGeorgios Giamas
LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer, including breast, lung, gastric, and colorectal cancer. It is local-ized in different cellular compartments, but its nuclear function has not been investigated so far. We mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are corre-lated with repressive chromatin markers. We further identi?ed KRAB-associated protein 1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interac-tion is stabilized by PP1a, which suppresses KAP1 phosphorylation speci?cally at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumor suppressor-like genes. Furthermore, LMTK3 functions at distal regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modi?cation and gene silencing. In sum-mary, we propose a model where a scaffolding func-tion of nuclear LMTK3 promotes cancer progression through chromatin remodeling.