2004 Fiscal Year Final Research Report Summary
Molecular mechanism of endosomal sorting of growth factors and receptors
| Project/Area Number |
15370053
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | Tokyo Institute of Technology |
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Principal Investigator |
KITAMURA Naomi Tokyo Institute of Technology, Graduate School of Bioscience & Biotechnology, Professor, 大学院・生命理工学研究科, 教授 (80107424)
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| Project Period (FY) |
2003 – 2004
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| Keywords | growth factor / growth factor receptor / early endosome / sorting / Hrs / STAM / deubiquitinating enzyme UBPY / ALG-2 |
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| Research Abstract |
Upon stimulation with growth factors, their receptors are rapidly internalized as a complex with bound ligands, and are transported to the endosome. From the endosome, ligand-bound receptors are transported to the lysosome for degradation. In this study, we examined the molecular mechanisms how Hrs and STAM regulate the endosomal sorting of growth factor/receptor complexes, and obtained the following results.
1.STAM mutants lacking the Hrs-binding activity were defective in causing the enlargement of early endosomes, accumulating ubiquitinated proteins on this aberrant organelle, and inhibiting the degradation of ligand-activated epidermal growth factor receptors(EGFR). These results indicate that association with Hrs on the early endosome is a prerequisite for STAM function.
2.Overexpression of a deubiquitinating enzyme UBPY that is a STAM binding protein, reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. In contrast overexpression of a catalytically-inactive UBPY mutant did not show such effects. These results indicate that UBPY plays an important role through reduction of the ubiquitination level of EGFR in regulation of EGFR sorting.
3.ALG-2 was identified as a novel Hrs-binding protein by a yeast two-hybrid screening. Hrs, ALG-2 and an ALG-2 binding protein Alix were bound in a Ca^<2+>-dependent manner. Treatment of cells with a Ca^<2+> ionophore induced colocalization of these proteins to the early endosome. These results suggest that Hrs regulates endosomal sorting by recruiting Alix through ALG-2 to the early endosome in a Ca^<2+>-dependent manner.
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Research Products
(12 results)
