In the last funding period, we have successfully completed all three proposed aims. Using nuclear HER2 (ErbB2) as a model, we extended our investigation to nuclear EGFR and much progress has been made. The current competitive renewal proposal is to further investigate the novel functions of nuclear EGFR and molecular mechanism of EGFR trafficking from the cell surface to the nucleus. We previously reported that the EGFR complex recognizes and binds to an AT-rich sequence (ATRS) of cyclin D1 transcription. Later, we demonstrated that EGFR interacts with STAT3 in the nucleus and the EGFR/STAT3 complex recognizes the ATRS and STAT binding sequence of the iNOS promoter and co-regulates the transcription of the iNOS gene. Both cyclin D1 and iNOS contribute to tumor progression raising the possibility that nuclear EGFR may be involved in tumor progression. In support of this, we and others have shown that nuclear EGFR correlates with poor clinical outcomes in breast, ovarian, esophagus, and oral cancers. We showed that nuclear EGFR interacts with PCNA, a well-known nucleus-specific antigen and phosphorylates the chromatin-bound PCNA at Tyr-211 residue resulting in stabilization of active PCNA and stimulation of DNA replication. In addition, we identified several interesting proteins interacting with EGFR in the nucleus including RHA and the SWI/SNF complex. RHA is a DNA-binding protein that recognizes the DNA sequence identical to the ATRS sequence and may be a potential candidate to be a DNA-binding partner of nuclear EGFR, which does not have a DNA-binding domain. SWI/SNF is a protein complex involved in chromatin remodeling. These newly identified EGFR interacting proteins have been shown to play a role in tumor progression. Finally, extending our observation that endocytosis and the nuclear pore complex (NPC) are involved in the nuclear translocation from cell surface for both EGFR and HER2 we have preliminary results to suggest that a retrograde transport mechanism is involved in the trafficking of cell surface EGFR to the nucleus. Thus, we hypothesize that nuclear EGFR contributes to tumor progression through transcriptional upregulation of tumor promoting genes and interacting with critical protein complexes involved in chromatin remodeling. The long-term goal of this proposal is to understand the novel functions of nuclear EGFR and their roles in the tumor progression.
Three specific Aims are proposed:
Specific Aim 1 : Transcriptional regulation and tumor progression of nuclear EGFR;
Specific Aim 2 : Nuclear EGFR and chromatin remodeling complex SWI/SNF in breast tumor development;
Specific Aim 3 : Molecular mechanism of EGFR trafficking from cell surface to nucleus. As EGFR has long been considered a cell surface receptor, its nuclear functions have been overlooked for decades. With increasing evidence of receptor tyrosine kinases in the nucleus and gradual discovery of their nuclear functions and prognostic value of nuclear EGFR in multiple human cancers, the current proposal represents a timely project that addresses the critical but "almost neglected" issues.
The long-term goal of this proposal is to understand the novel functions of nuclear EGFR and their roles in the tumor progression. With increasing evidence of receptor tyrosine kinases in the nucleus and gradual discovery of their nuclear functions including prognostic value of nuclear EGFR in multiple human cancers, the current proposal represents a timely project that addresses the critical but almost forgotten issues.
|Thirumurthi, Umadevi; Shen, Jia; Xia, Weiya et al. (2014) MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer. Sci Signal 7:ra71|
|Chou, Chao-Kai; Lee, Heng-Huan; Tsou, Pei-Hsiang et al. (2014) mMAPS: a flow-proteometric technique to analyze protein-protein interactions in individual signaling complexes. Sci Signal 7:rs1|
|Chou, Ruey-Hwang; Wang, Ying-Nai; Hsieh, Yi-Hsien et al. (2014) EGFR modulates DNA synthesis and repair through Tyr phosphorylation of histone H4. Dev Cell 30:224-37|
|Yamaguchi, H; Chang, S-S; Hsu, J L et al. (2014) Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene 33:1073-81|
|Hsu, Yi-Hsin; Yao, Jun; Chan, Li-Chuan et al. (2014) Definition of PKC-?, CDK6, and MET as therapeutic targets in triple-negative breast cancer. Cancer Res 74:4822-35|
|Du, Y; Shen, J; Hsu, J L et al. (2014) Syntaxin 6-mediated Golgi translocation plays an important role in nuclear functions of EGFR through microtubule-dependent trafficking. Oncogene 33:756-70|
|Yu, Yung-Luen; Chou, Ruey-Hwang; Liang, Jia-Hong et al. (2013) Targeting the EGFR/PCNA signaling suppresses tumor growth of triple-negative breast cancer cells with cell-penetrating PCNA peptides. PLoS One 8:e61362|
|Shen, Jia; Xia, Weiya; Khotskaya, Yekaterina B et al. (2013) EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2. Nature 497:383-7|
|Yamaguchi, Hirohito; Hsu, Jennifer L; Chen, Chun-Te et al. (2013) Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells. Clin Cancer Res 19:845-54|
|Yu, Yung-Luen; Chou, Ruey-Hwang; Shyu, Woei-Cherng et al. (2013) Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke. EMBO Mol Med 5:531-47|
Showing the most recent 10 out of 65 publications