Abstract
The membrane-anchored Src tyrosine kinase is involved in numerous pathways and its deregulation is involved in human cancer. Our knowledge on Src regulation relies on crystallography, which revealed intramolecular interactions to control active Src conformations. However, Src contains a N-terminal intrinsically disordered unique domain (UD) whose function remains unclear. Using NMR, we reported that UD forms an intramolecular fuzzy complex involving a conserved region with lipid-binding capacity named Unique Lipid-Binding Region (ULBR), which could modulate Src membrane anchoring. Here we show that the ULBR is essential for Src’s oncogenic capacity. ULBR inactive mutations inhibited Src transforming activity in NIH3T3 cells and in human colon cancer cells. It also reduced Src-induced tumor development in nude mice. An intact ULBR was required for MAPK signaling without affecting Src kinase activity nor sub-cellular localization. Phospho-proteomic analyses revealed that, while not impacting on the global tyrosine phospho-proteome in colon cancer cells, this region modulates phosphorylation of specific membrane-localized tyrosine kinases needed for Src oncogenic signaling, including EPHA2 and Fyn. Collectively, this study reveals an important role of this intrinsically disordered region in malignant cell transformation and suggests a novel layer of Src regulation by this unique region via membrane substrate phosphorylation.
Highlights
Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase, which mediates signaling induced by a wide range of cell surface receptors, leading to cell growth and adhesion [1]
We uncover an important role of this molecular property made by Src-unique domain (UD) in cancer development
The biological roles of intrinsically disordered region (IDR) contained in Src Family Kinases (SFKs) have remained unclear, despite strong insight into Src regulation
Summary
Originally identified as an oncogene, is a membrane-anchored tyrosine kinase, which mediates signaling induced by a wide range of cell surface receptors, leading to cell growth and adhesion [1]. Src shares with the other Src Family Kinases (SFKs) a common modular structure formed by the membrane-anchoring SH4 region followed by an intrinsically disordered region (IDR) named unique domain (UD), and the SH3, SH2, and kinase domains [2]. Early studies reported that the whole UD deletion does not affect Src oncogenic activity [7], which suggests that this region may not play an important role in Src signaling. While considerable insight into Src regulation has been provided since the discovery of the Src oncogene, the functional role of its unstructured region remains unclear
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