Research interests


Cancer initiation and progression

An emerging theme in cancer biology is the dependence of cancer subtypes on certain signaling pathways for continued tumor growth. For example, mutations that activate the Hedgehog signaling pathway drive growth of a variety of cancers including basal cell carcinoma (BCC), medulloblastoma, pancreatic, prostate, and small cell lung cancer that account for up to 25% of all human cancer deaths. Despite the critical nature of Hedgehog signaling, how Hedgehog mediates tumor proliferation remains poorly understood. Although use of antagonists that target the Hedgehog pathway GPCR Smoothened are effective in treating advanced or metastatic BCC, over 50% of advanced tumors harbor innate resistance and over 20% of tumors that initially respond to drug acquire resistance, illustrating the need for additional targets for therapy. Our lab has identified the oncogene atypical Protein Kinase C (aPKC) as a novel Hedgehog target gene and activator of Hedgehog signaling. aPKC forms a positive feedback loop by phosphorylating and activating the transcription factor GLI1, resulting in an increase in DNA binding and transcriptional activity. Sensitive and drug resistant BCCs magnify aPKC activity to drive high levels of pathway activation and therapeutic use of aPKC inhibitors selectively suppress Hedgehog signaling and tumor growth. Projects in the lab include determining how tumor cells regulate kinase activity, identifying novel kinase-substrate interactions that drive tumor growth, and creating novel inhibitors to target these pathways.


Cell fate specification

Complex tissues and cellular architecture develop and are maintained by cell fate specification of stem cells. Typically, stem cells set up a gradient of polarized components that function to organize interior and exterior structures and signaling factors, allowing daughter cells to adopt specific fates and perform specialized functions. This process of cell polarity drives a diverse range of functions such as maintaining the epithelial barrier, cell-to-cell communication, motility, and stem cell self-renewal and differentiation. The conserved oncogene aPKC is a master regulator of cell polarity and fate specification and is found in virtually all polarized systems. A newly appreciated aspect of aPKC is the ability to target transcription factors to regulate the genetic landscape of the cell. Although transcription factors spatially and temporally bind DNA, how posttranslational modifications control transcription factor function is poorly understood. Our lab has found that aPKC phosphorylates the C2H2 zinc finger domain of GLI1 to promote DNA binding and transcriptional activity, an exceedingly rare event that positively regulates transcription factor function. Projects in the lab include how phosphorylation serves as a general transcription factor regulatory mechanism, how kinase-transcription factor interactions specify the skin and hair follicle, and how cancers co-opt this developmental process to drive tumor growth.

Cerebellar dysfunction

The cerebellum is an attractive system to study signaling mechanisms that allow diverse neuronal fates arising from neural stem cells at spatially and temporally defined niches. Motor learning, sensory control, and cognitive function derive from the cerebellum and dysregulation leads to a variety of diseases such as cerebellar ataxia and medulloblastoma. The molecular mechanisms behind cerebellar ataxia originating from Purkinje cell degeneration are largely unknown despite the growing genetic characterization of the disease. Our lab has found that the oncogene Missing-in-Metastasis (MIM) regulates Purkinje cell survival. MIM is an I-BAR containing scaffold protein that links membrane dynamics to the actin cytoskeleton and is highly expressed in Purkinje cells. We generated a conditional knockout of MIM in mice and found a progressive degeneration of coordination and movement that resulted from early Purkinje cell loss, with 80% of cells lost at three months and accompanied by reactive gliosis. MIM suppresses kinases such as Src and aPKC, and we find that Src inhibitors can partially rescue Purkinje cell loss. Projects in the lab include determining MIM’s function in the cerebellum, how kinase signaling regulates Purkinje cell homeostasis and gene regulation, and exploring the connections to human ataxias and medulloblastoma.