Abstract
To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that ubiquitin domain-containing protein 1 (UBTD1) plays a crucial role in both the epidermal growth factor receptor (EGFR) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through N-acylsphingosine amidohydrolase 1 (ASAH1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of Sequestosome 1 (SQSTM1/p62) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation.
Highlights
All living organisms perceive variations in their environment and translate them into intracellular signals via signaling pathways
We confirmed by western-blot an increase in epidermal growth factor receptor (EGFR) phosphorylation (Y1068 and Y1086) at steady state, and we noticed an increase in the total amount of EGFR in ubiquitin domain-containing protein 1 (UBTD1)-depleted cells (Figure 1B, Figure 1—figure supplement 1B)
To confirm that UBTD1 acts on p62/SQSTM1 ubiquitination via RNF26, we examined the interaction between p62/SQSTM1 and RNF26 in control and UBTD1depleted cells (Figure 6D, Figure 6—figure supplement 1C)
Summary
All living organisms perceive variations in their environment and translate them into intracellular signals via signaling pathways. Disturbances in this signal transduction mechanism induce inappropriate cell behavior and are associated with a plethora of diseases including cancer. Cellular signaling can be viewed as a finely tuned ‘space-time continuum’ (Scott and Pawson, 2009). Receptors activated by their ligands at the plasma membrane are endocytosed, moved
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