LMTK3 is an oncogenic receptor tyrosine kinase implicated in various types of cancer including breast, lung, gastric and colorectal. We have already demonstrated the contribution of LMTK3 in invasion, migration and transcriptional regulation as well as its involvement in endocrine resistance in breast cancer. Despite the significant progress in understanding the role of LMTK3 in human tumourogenesis, the signalling pathways implicated in LMTK3 regulation still remain to be elucidated.

Protein phosphorylation play an essential role in regulating intracellular signal transduction pathways involving almost every aspect of cell activity. In silico phosphoproteomic analysis predicted several potential LMTK3 phosphorylation sites targeted by different kinases including Cyclin-dependent kinase 5 (CDK5), a cytoplasmic proline-directed serine/threonine kinase that is commonly overexpressed in many solid tumours. Interestingly, recent work performed by two different groups showed that CDK5 is a regulator of LMTK1 and LMTK2 in neuronal cells, resulting in axonal outgrowth and potentially influencing a number of neurophysiological processes.

By performing a variety of molecular/cellular and biochemical experiments we confirmed the ability of CDK5 to phosphorylate LMTK3 in vitro and identified its exact phosphorylation sites. Moreover, we investigated the consequences of CDK5 phosphorylation on various LMTK3 processes, amongst which its stability, sub-cellular localization, its ability to interact with chromatin and others. In addition, the clinical correlation of CDK5 and LMTK3 expression in cell lines and patients’ samples were assessed. In aggregate, we describe a new cellular pathway encompassing CDK5 and LMTK3 that results in breast cancer tumour progression.

Our data will be presented.

Citation Format: Giulia Lucchiari, Hua Zhang, Joao Nunes, Yichen Xu, Arnhild Grothey, Justin Stebbing, Georgios Giamas. Role of phosphorylation in Lmtk3 activation and its contribution in breast cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 185.