Fig 1: Proposed model of trafficking of EGFR cross-linked by Sym004. EGF promotes strong EGFR phosphorylation and Cbl-dependent ubiquitylation leading to synchronised, dynamin-dependent and clathrin-dependent and -independent internalisation, followed by fast and coordinated delivery to LEs/MVBs and ESCRT-dependent lysosomal degradation; both EGFR TK activity and p38 activity contribute to this process. Sym004-mediated EGFR internalisation is slow and asynchronous, partially depends on clathrin, dynamin activity and actin polymerisation, but does not require EGFR TK activity, p38 activity, Cbl ubiquitin ligases or EGFR ubiquitylation. Although the ESCRT machinery is required for EGFR degradation upon Sym004, it is likely important for LEs/MVBs formation per se rather than for recognition of non/negligibly-ubiquitylated EGFR. We propose that cross-linking of multiple EGFR molecules by Sym004 physically triggers EGFR endocytosis, leading to lysosomal degradation of both EGFR and Sym004. TK, tyrosine kinase; PM, plasma membrane, Les/MVBs, late endosomes/multivesicular bodies.