Research Papers:

Pro-oncogenic function of HIP-55/Drebrin-like (DBNL) through Ser269/Thr291-phospho-sensor motifs

Zijian Li _, Hae Ryon Park, Zhi Shi, Zenggang Li, Cau Dinh Pham, Yuhong Du, Fadlo R. Khuri, Youyi Zhang, Qide Han and Haian Fu

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Oncotarget. 2014; 5:3197-3209. https://doi.org/10.18632/oncotarget.1900

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Zijian Li1,2*, Hae Ryon Park1, Zhi Shi1, Zenggang Li1, Cau Dinh Pham1, Yuhong Du1, Fadlo R. Khuri3, Youyi Zhang2, Qide Han2, and Haian Fu1,3*

1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA

2 Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191, China

3 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, 30322, USA


Zijian Li, email:

Haian Fu, email:

Keywords: HIP-55, DBNL, HPK1, 14-3-3, tumorigenesis, signal transduction

Received: January 06, 2014 Accepted: April 16, 2014 Published: April 16, 2014


HIP-55 (HPK1-interacting protein of 55 kDa, also named DBNL, SH3P7, and mAbp1) is a multidomain adaptor protein that is critical for organ development and the immune response. Here, we report the coupling of HIP-55 to cell growth control through its 14-3-3-binding phospho-Ser/Thr-sensor sites. Using affinity chromatography, we found HIP-55 formed a complex with 14-3-3 proteins, revealing a new node in phospho-Ser/Thr-mediated signaling networks. In addition, we demonstrated that HIP-55 is required for proper cell growth control. Enforced HIP-55 expression promoted proliferation, colony formation, migration, and invasion of lung cancer cells while silencing of HIP-55 reversed these effects. Importantly, HIP-55 was found to be upregulated in lung cancer cell lines and in tumor tissues of lung cancer patients. Upregulated HIP-55 was required to promote the growth of tumors in a xenograft animal model. However, tumors with S269A/T291A-mutated HIP-55, which ablates 14-3-3 binding, exhibited significantly reduced sizes, supporting a vital role of the HIP-55/14-3-3 protein interaction node in transmitting oncogenic signals. Mechanistically, HIP-55-mediated tumorigenesis activity appears to be in part mediated by antagonizing the tumor suppressor function of HPK1. Thus, the HIP-55–mediated oncogenic pathway, through S269/T291, may be exploited for the development of new therapeutic strategies.

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