Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin ?1 and CRM1

ASIA unversity > 醫學暨健康學院 > 生物科技學系 > 期刊論文 > Item 310904400/4594

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Title:	Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin ?1 and CRM1
Authors:	Lo, H-W.;Seyed-Mohamed, A.;Wu, Y.;Bartholomeusz, G.;Hsu, S-C.;Mien-Chie Hung
Keywords:	EGF receptor;importin 1;endocytosis;endosomal sorting;CRM1;cancer
Date:	2006-04
Issue Date:	2009-11-27 13:56:59 (UTC+8)
Publisher:	Asia University
Abstract:	Many receptor tyrosine kinases (RTKs) can be detected in the cell nucleus, such as EGFR, HER-2, HER-3, HER-4, and fibroblast growth factor receptor. EGFR, HER-2 and HER-4 contain transactivational activity and function as transcription co-factors to activate gene promoters. High EGFR in tumor nuclei correlates with increased tumor proliferation and poor survival in cancer patients. However, the mechanism by which cell-surface EGFR translocates into the cell nucleus remains largely unknown. Here, we found that EGFR co-localizes and interacts with importins 1/1, carriers that are critical for macromolecules nuclear import. EGFR variant mutated at the nuclear localization signal (NLS) is defective in associating with importins and in entering the nuclei indicating that EGFR's NLS is critical for EGFR/importins interaction and EGFR nuclear import. Moreover, disruption of receptor internalization process using chemicals and forced expression of dominant-negative Dynamin II mutant suppressed nuclear entry of EGFR. Additional evidences suggest an involvement of endosomal sorting machinery in EGFR nuclear translocalization. Finally, we found that nuclear export of EGFR may involve CRM1 exportin as we detected EGFR/CRM1 interaction and markedly increased nuclear EGFR following exposure to leptomycin B, a CRM1 inhibitor. Collectively, these data suggest the importance of receptor endocytosis, endosomal sorting machinery, interaction with importins 1/1, and exportin CRM1 in EGFR nuclear-cytoplasmic trafficking. Together, our work sheds light into the nature and regulation of the nuclear EGFR pathway and provides a plausible mechanism by which cells shuttle cell-surface EGFR and potentially other RTKs through the nuclear pore complex and into the nuclear compartment. J. Cell. Biochem
Relation:	JOURNAL OF CELLULAR BIOCHEMISTRY 98(6):1570-1583
Appears in Collections:	[生物科技學系] 期刊論文

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