Regulation of Src tumor activity by its N-terminal intrinsically disordered region

• Published in: Oncogene Vol. 41; no. 7; pp. 960 - 970
• Main Authors: Aponte, Emilie, Lafitte, Marie, Sirvent, Audrey, Simon, Valérie, Barbery, Maud, Fourgous, Elise, Boublik, Yvan, Maffei, Mariano, Armand, Florence, Hamelin, Romain, Pannequin, Julie, Fort, Philippe, Pons, Miquel, Roche, Serge
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.02.2022; Nature Publishing Group; Nature Publishing Group [1987-....]
• Subjects: 101/58; 13; 13/95; 14; 42; 45/70; 631/67/395; 631/80/86/2368; 64/60; 96; Animals; Apoptosis; Cancer; Cell Biology; Cell Line, Tumor; Cellular Biology; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Crystallography; EphA2 protein; Fyn protein; Human Genetics; Humans; Internal Medicine; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - genetics; Intrinsically Disordered Proteins - metabolism; Kinases; Life Sciences; Localization; MAP kinase; Medicine; Medicine & Public Health; Mice; Mice, Nude; NIH 3T3 Cells; NMR; Nuclear magnetic resonance; Oncology; Phosphorylation; Protein Domains; Protein-tyrosine kinase; Proteomes; Proteomics; src-Family Kinases - genetics; src-Family Kinases - metabolism; Tumors
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-02092-x

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.