title: Pro-oncogenic function of HIP-55/Drebrin-like (DBNL) through Ser269/Thr291-phospho-sensor motifs.
abstract: 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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Li
authors.forename: Hae Ryon
authors.initials: HR
authors.lastname: Park
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.forename: Zenggang
authors.initials: Z
authors.lastname: Li
authors.forename: Cau Dinh
authors.initials: CD
authors.lastname: Pham
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qide
authors.initials: Q
authors.lastname: Han
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002846:Chromatography, Affinity; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness / Q000473:pathology; D010766:Phosphorylation; D034741:RNA, Small Interfering; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014162:Transfection; D018909:src Homology Domains
chemical_list: D048948:14-3-3 Proteins; C117063:DBNL protein, human; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D013912:Threonine; D012694:Serine