New protein involved in growth factor downregulation discovered
Ingrid Roxrud
A new ubiquitin-binding protein that mediates sorting of endocytosed growth factor receptors from endosomes to lysosomes has been discovered by scientists from Harald Stenmark's group at the Institute for Cancer Research, as reported in the latest issue of the Journal of Cell Biology (impact factor 10.152) - published online 24 March 2008. First author is Ingrid Roxrud (photo).
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.
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)
Meriranta L, Sorri S, Huse K, Liu X, Spasevska I, Zafar S, Chowdhury I, Dufva O, Sahlberg E, Tandaric L, Karjalainen-Lindsberg ML, Hyytiainen M, Varjosalo M, Myklebust JH, Leppa S(2024) Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-cell Lymphoma Blood Cancer Discov(in press) DOI 10.1158/2643-3230.BCD-23-0182, PubMed 38630892
Grindedal EM, Zucknick M, Stormorken A, Rønne E, Tandstad NM, Isaacs WB, Axcrona K, Mæhle L(2024) Outcomes of 10 years of PSA screening for prostate cancer in Norwegian men with Lynch syndrome Prostate(in press) DOI 10.1002/pros.24711, PubMed 38629217
Suske T, Sorger H, Manhart G, Ruge F, Prutsch N, Zimmerman MW, Eder T, Abdallah DI, Maurer B, Wagner C, Schönefeldt S, Spirk K, Pichler A, Pemovska T, Schweicker C, Pölöske D, Hubanic E, Jungherz D, Müller TA, Aung MMK, Orlova A, Pham HTT, Zimmel K, Krausgruber T, Bock Cet al.(2024) Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia J Clin Invest, 134(8) DOI 10.1172/JCI168536, PubMed 38618957
