New protein involved in growth factor downregulation discovered
Ingrid Roxrud
When cells are exposed to high levels of growth factors, the growth factor receptors become internalized by endocytosis and subsequently degraded in lysosomes as a mechanism to prevent overactivation of growth factor signalling pathways that mediate cell proliferation. Because growth factor signalling is often strongly upregulated in cancers, researchers are trying to elucidate the molecular mechanisms of growth factor-induced receptor downregulation.
It has been known for some time that a protein called Eps15 facilitates endocytosis of epidermal growth factor receptors (EGFRs). Now, PhD student Ingrid Roxrud in Harald Stenmark's group has identified a "cousin" of Eps15, called Eps15b, which plays a different role in EGFR downregulation.
While Eps15 works at the plasma membrane, Eps15b works at early endosomes (see Figure), where it binds to the sorting protein Hrs and mediates sorting of EGFRs to lysosomes for degradation. EGFRs are known to become ubiquitinated when activated by growth factor, and both Eps15b and Hrs are ubiquitin binding proteins that presumably interact directly with the ubiquitinated receptor to mediate its sorting.
Links:
An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor
Ingrid Roxrud, Camilla Raiborg, Nina Marie Pedersen, Espen Stang and Harald Stenmark
The Journal of Cell Biology, Vol. 180, No. 6, 1205-1218
Published online 24 March 2008
Harald Stenmark's group
Departement of Biochemistry
Insitute for Cancer Research
It has been known for some time that a protein called Eps15 facilitates endocytosis of epidermal growth factor receptors (EGFRs). Now, PhD student Ingrid Roxrud in Harald Stenmark's group has identified a "cousin" of Eps15, called Eps15b, which plays a different role in EGFR downregulation.
While Eps15 works at the plasma membrane, Eps15b works at early endosomes (see Figure), where it binds to the sorting protein Hrs and mediates sorting of EGFRs to lysosomes for degradation. EGFRs are known to become ubiquitinated when activated by growth factor, and both Eps15b and Hrs are ubiquitin binding proteins that presumably interact directly with the ubiquitinated receptor to mediate its sorting.
Together with AP2, Epsin, and several other proteins, Eps15 mediates internalization of activated EGFRs. The endocytosed receptors and their ligands are then transported to early endosomes, where they are retained in a clathrin coat by Hrs, STAM, and Eps15b. They are further escorted into intraluminal vesicles of multivesicular endosomes and finally degraded in lysosomes (not depicted). (click to enlarge image)
Links:
An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor
Ingrid Roxrud, Camilla Raiborg, Nina Marie Pedersen, Espen Stang and Harald Stenmark
The Journal of Cell Biology, Vol. 180, No. 6, 1205-1218
Published online 24 March 2008
Harald Stenmark's group
Departement of Biochemistry
Insitute for Cancer Research
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