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.
Highlights
The proper growth of mammalian cells is controlled by well-coordinated signal transduction pathways and networks
By manipulating the levels of HIP-55 in cells and in a xenograft animal system, our studies reveal a role of HIP-55 in cell growth control, and suggest the potential importance of dysregulated HIP-55 in tumorigenesis and tumor progression through a mechanism involving the 143-3 binding phospho-sensor sites, S269 and T291
Overexpression of HIP-55 reversed this effect (Figure 2G). These results demonstrate that HIP55 promotes cell growth and enhances the anchorage-independent survival of lung cancer cells, and support a role for HIP-55 in promoting tumorigenesis
Summary
The proper growth of mammalian cells is controlled by well-coordinated signal transduction pathways and networks. The adaptor protein Grb contains an SH2 domain that binds phosphorylated Tyr and SH3 domains, which bind Pro-rich structures In this configuration, Grb transmits signals to downstream effectors to promote cell proliferation upon growth factor stimulation. The family of 14-3-3 proteins can recognize phosphorylated Ser/ Thr motifs to exert diverse regulatory functions [4,5,6,7,8]. Because of their vital role in controlling cell signaling, dysregulation of adaptor proteins, including 14-3-3, have been implicated in diverse diseases, including cancer. The identification of adaptor proteins that are associated with growth control may reveal new www.impactjournals.com/oncotarget mechanisms that regulate cell proliferation under normal physiological conditions, as well as in cancer
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