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Hipk: a versatile regulator of multiple signaling networks during Drosophila development

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(Thesis) Ph.D.
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Author: Lee, Wendy
Development of multicellular organisms is a dynamic process that requires cell-cell communication through the transmission of signal transduction pathways. Signaling cascades elicit transcriptional programs to synchronize discrete biological processes to pattern a multicellular organism. These signals are tightly regulated and their deregulation can lead to cancer onset and progression. Homeodomain interacting protein kinases (Hipks) represent a family of serine/threonine kinases. Members of this group (in particular Hipk2) have been implicated as important factors in transcriptional regulation to control cell growth, apoptosis and development. These studies identified an essential requirement for the sole Drosophila member of this family, Hipk. Genetic and phenotypic analysis revealed novel roles for Hipk in the Notch and Wingless (Wg) pathway. Specifically, Hipk utilizes diverse mechanisms to regulate gene transcription depending on the cellular context. In the developing eye, Hipk stimulated the early function of Notch mediated growth. Consistent with this model, genetic interaction analyses demonstrated that Hipk phosphorylates the global co-repressor Groucho (Gro) to relieve its inhibitory effect on Notch, thereby promoting the Notch signal. In addition, loss of hipk led to reduced expression of Notch targets, including the growth promoting factor, Eyegone (Eyg). Furthermore, overexpression of Hipk led to overgrown visual organs in both the adult and larval tissue. A similar role for Hipk in promoting growth in additional tissues was also observed, this likely represents a general role for Hipk in growth. Genetic and phenotypic evidence in the wing demonstrated a role for Hipk as a positive regulator in the Wg pathway. Mutant and misexpression analyses in the wing demonstrate that Hipk promotes Wg signaling through Armadillo (Arm) stability and stimulation of Wg target gene expression. Consistent with these observations, Hipk enhanced Tcf/Arm-mediated gene expression in cell culture. In addition, Hipk can bind to Arm and Tcf, and phosphorylate Arm. Using both in vitro and in vivo assays, Hipk was found to promote the stabilization of Arm. Similar molecular interactions between Lef1/β-catenin and vertebrate Hipk2 were observed, suggesting a conserved role for Hipks in promoting Wnt signaling. These studies reveal that Hipk is a key regulator of multiple signaling networks during development.
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