Tau-tubulin kinase 1 (TTBK1) is a CNS-specific kinase that has been implicated in the pathological phosphorylation of tau in Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD). TTBK1 is a challenging therapeutic target because it shares a highly conserved catalytic domain with its homolog, TTBK2, a ubiquitously expressed kinase genetically linked to the disease spinocerebellar ataxia type 11. Unbiased identification of list of neuronal interactors and phosphorylation substrates for TTBK1 and TTBK2 highlight unique cellular pathways and functional networks that each isoform is involved in and help us understand them as distinct targets for the treatment of neurodegenerative diseases.

Our research involves defining novel kinase drivers in 3q amplicon-positive squamous cell carcinomas and the mechanisms by which these kinases promote cancer. Our previous work has led us to focus on leucine zipper bearing kinase (LZK, also known as MAP3K13) and TRAF2- and NCK-interacting kinase (TNIK) as therapeutic targets in head and neck squamous cell carcinomas (HNSCCs) and lung squamous cell carcinomas (LSCCs).

Protein phosphorylation is a widespread PTM. Here we profiled the substrate specificity of the human Ser/Thr kinome. We used our dataset to computationally identify the kinases capable of phosphorylating any Ser/Thr site. When this approach was applied to examine cellular signaling responses to targeted inhibitors, it revealed insights into pathway complexity and compensation. Overall, these studies provide a resource for exploring the cellular effects of kinase inhibitors in great detail.

New pharmacologic strategies to stimulate bone formation for patients with osteoporosis are needed. Salt inducible kinases (SIKs) play key roles in mediating the effects of parathyroid hormone in target cells in bone and mineral metabolism. Intracellular cAMP signaling leads to PKA-mediated inhibition of SIK cellular function. Therefore, direct SIK inhibitors may mimic the actions of parathyroid hormone and other cAMP-linked GPCR pathways. Potent and specific small molecule SIK inhibitors may represent a promising new ‘bone anabolic’ approach for osteoporosis and related disorders.

Signaling pathways that regulate ion channel macromolecular complexes are critical for neuronal plasticity. Glycogen synthase kinase 3ß (GSK3ß) has been linked to neuronal plasticity, in a way consistent with a scaffolding role in the voltage-gated Na+ channel Nav1.6 complex. Evidence will be shown for small molecules which target GSK3ß/Nav1.6 and can modulate plasticity without impacting kinase activity. These studies are the foundation for developing new neurotherapeutic approaches towards GSK3ß.

ULK3 is a nuclear kinase with elevated expression in squamous cell carcinomas. ULK3 gene silencing or deletion reduces clonogenicity of human keratinocytes and SCC-derived cells. It recruits the activity of two histone arginine methyltransferases, PRMT1 and PRMT5, to specific stem cell-related and metabolism genes. Downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the tumorigenic potential of SCC cells in vivo.

We developed a potent and specific RIPK1 degrader LD4172 that synergizes with anti-PD1 to trigger immunogenic cell death and significantly inhibit tumor growth in immunotherapy resistant syngeneic mouse models. The synergistic effect of LD4172 and anti-PD1 can be reversed by blocking either CD19, BAFFR, CD8, or CD40L, demonstrating that both B and T cells and their crosstalk play important roles in the antitumor immunity.