GSE70385
LMTK3 Represses Tumour Suppressor-Like Genes through Chromatin Remodeling in Breast Cancer
LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer including breast, lung, gastric and colorectal. It is localized in different cellular compartments but its nuclear function has not been investigated thus far. We have mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB associated protein-1 (KAP1) as a novel binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1_, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumour suppressor-like genes. Furthermore, LMTK3 functions at enhancer regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a new model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling, revealing a new mechanism of RTK activity. Overall design: Examination of LMTK3 binding profile in 2 cell types.