Research

Primary cilia are “cellular antennae” and signaling hubs that amplify and integrate multiple chemical inputs such as calcium and cyclic AMP signaling responses within their specialized organellar environment. Ciliopathies are a group of disorders associated with genetic mutations in proteins, that result in either abnormal formation or function of cilia. Hence, understanding which second messenger...

Fibrolamellar carcinoma (FLC) is a rare adolescent liver cancer with unique molecular features. FLC emanates from a genetic lesion on chromosome 19 that generates a de novo fusion gene product consisting of the chaperonin-binding domain of Hsp40 (DNAJ), and the catalytic subunit of PKA. Recent work in the Scott lab has found that this chimeric...

A positive prognosis for breast cancer is less certain when primary tumors metastasize.  Many signaling pathways that converge on mitochondrial function are engaged during metastasis.  Through screening of deidentified cancer patient databases we have detected an inverse relationship between the expression of outer mitochondrial membrane associated anchoring protein dAKAP1 and breast cancer.  Genetic depletion of...

Mitch Omar and Tyler Lakey Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. We define mechanisms of action for the PKAc-L205R and W196R variants. Proximity proteomic techniques demonstrate that both Cushing’s mutants are excluded from A kinase anchoring protein (AKAP) signaling islands, whereas live-cell photoactivation...

Most cells typically express 15-20 different AKAPs, thereby creating an archipelago of signaling islands that can simultaneously propagate individual second messenger signaling events. The importance of this local signaling mechanism is underscored by evidence that loss of AKAP-mediated enzyme targeting disrupts essential physiological processes such as learning and memory, cardiac function, and insulin release. For...

AKAP signaling islands constrain protein kinase A (PKA) and other effector proteins at specific regions of the cell. PKA anchoring is mediated by protein-protein interactions between the docking and dimerization domain of the regulatory subunits and an amphipathic helix of the AKAP. Preferential binding of the type I or the type II regulatory subunits to...

Hormones often transmit signals through adenosine 3’,5’-monophosphate (cAMP) cascades to promote protein phosphorylation at precise intracellular locations.  The fidelity of these responses relies on the activation of anchored protein kinase A (PKA) holoenzymes.  Using single-particle electron microscopy and other structural approaches we demonstrated that the anchoring protein AKAP79 constrains RII-C sub-assemblies within 150 to 250Å...

Protein interaction domains create unique macromolecular complexes that drive evolution.  By combining phylogenetic analyses with structural approaches, we have discovered that the docking and dimerization (D/D) domain of the protein kinase A regulatory (PKA-R) subunit is an ancient protein fold.  Homology searching reveals a D/D domain superfamily with eighteen members that are conserved across most...

Intracellular diffusion of chemical signals is a molecular basis of cellular communication.  This theory was originally predicated on the notion that all regulatory enzymes are soluble and move with a Brownian motion.  Yet, these enzymes often have different roles in distinct subcellular compartments.  Thus, compartmentalization of enzymes is now recognized as an important molecular mechanism...