biostudies-literatureMohammad ILLigue Contre le CancerAgence Nationale de la RechercheMEC | Agencia Estatal de InvestigaciónCentro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicinae202403019https://www.ebi.ac.uk/biostudies/studies/S-EPMC11909415biostudies-literatureUnknown8(5)Src tyrosine kinase regulates cell growth and adhesion through membrane signaling, and its deregulation is associated with cancer. Although active Src is anchored to the plasma membrane, the role of membrane lipids in its regulation remains unclear. Here, we report that Src self-associates via a lysine cluster in its SH4 region, a process mediated by lipids in human cells and in vitro. Mutation of the lysine cluster to arginine alters Src self-association and modulates its transforming function in human cells. Lipid-anchored micron-sized condensates of full-length Src form in supported homogeneous lipid bilayers (i.e., independently of lipid phase separation). Condensates also arise from the purified Src N-terminal regulatory element, which includes the myristoylated SH4 domain, the intrinLife science allianceLipid-driven Src self-association modulates its transformation capacity.PMC11909415CB06/01/008PID2019-104914RB-I00, PDC2021-121629-I00, PID2022-139160OB-I00PID2022-140459OB-I00INCa-DGOSInserm6045FUZZY-SRC ANR-21-CE13-011Sirvent APons MBoublik YGiannotti MIFourgous ELe Roux ALMohammad ILTaules MRoche SFernandez AfalseLipid-driven Src self-association modulates its transformation capacity.Src tyrosine kinase regulates cell growth and adhesion through membrane signaling, and its deregulation is associated with cancer. Although active Src is anchored to the plasma membrane, the role of membrane lipids in its regulation remains unclear. Here, we report that Src self-associates via a lysine cluster in its SH4 region, a process mediated by lipids in human cells and in vitro. Mutation of the lysine cluster to arginine alters Src self-association and modulates its transforming function in human cells. Lipid-anchored micron-sized condensates of full-length Src form in supported homogeneous lipid bilayers (i.e., independently of lipid phase separation). Condensates also arise from the purified Src N-terminal regulatory element, which includes the myristoylated SH4 domain, the intrin2025-01-01T00:00:00Z2025 May2026-07-15T05:42:31.337Z2025-04-04T03:04:08.329ZS-EPMC119094154008198710.26508/lsa.202403019