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Faculty Kimberly L. Dodge-Kafka
Assistant Professor of Cell Biology/Canter for Cardiology and
Cardiovascular Research
dodge@uchc.edu
Areas of Interest:
The second messenger cAMP plays a pivotal role in the regulation of
many biological processes in the heart, including calcium dynamics,
contraction, and gene transcription. With an increasing number of
hormones that stimulate cAMP production as well as the identification of
a multitude of targets for cAMP-mediated pathways, an intriguing yet
complicated question is how specificity of signaling is ensured? In
other words, how does a particular hormone regulate a specific
phosphorylation event when it acts via a common second messenger? The
identification of scaffolding proteins that link upstream activators
with their downstream targets has provided a molecular framework that
allows for compartmentation of cAMP signaling pathways as well as the
orchestration of spatial-temporal control over phosphorylation events.
A-Kinase Anchoring Proteins (AKAPs) are prototypical examples of
scaffolding proteins that direct cAMP-responsive events while
coordinating the activity of multiple signaling enzymes. AKAPs bind the
regulatory subunit of the cAMP-dependent protein kinase and localize the
enzyme to discrete locations within the cell. Additionally, AKAPs
coordinate multiple signaling pathways through the anchoring of
additional signaling enzymes such as phosphatases, phosphodiesterases,
and other kinases.
My research focus is the understanding of how the specific
subcellular localization of signaling enzymes regulates cardiac
physiology. In particular, we have characterized a scaffolding protein
termed mAKAP and demonstrated its association with several signaling
enzymes including the protein phosphatase PP2A, the phosphodiesterase
PDE4D3, the cAMP-dependent protein kinase PKA, the Big Map Kinase ERK5,
and the transcription factor MEF2D. Furthermore, we have demonstrated
how association with the complex regulates the activities of ERK5,
PDE4D3 and PP2A. We are now investigating the contribution of these
mAKAP-bound enzymes for the induction of cardiac hypertrophy.
Lab Rotation Projects:
The research focus of the Dodge-Kafka laboratory is the understanding of
how the specific subcellular localization of signaling enzymes regulates
cardiac physiology and induction of cardiac disease. We use a variety of
techniques including luciferase assays, kinase/phosphodiesterase/phosphatase
assays, transfections, DNA manipulation, construction of adenoviral
vectors, co-immunoprecipitations, signal cell siRNA, site-directed
mutagenesis, and primary cell culture. Rotations in the lab include:
- Examining the molecular mechanisms that activate the transcription
factors involved in the induction of cardiac disease
- Molecular characterization of AKAP signaling complexes
- Determining the molecular architecture of cAMP signaling domains
in the heart
Other projects available and can be discussed depending on student’s
interests.
Selected Publications:
Jennifer J. Carlisle Michel, Ian K. Townley, Kimberly L. Dodge-Kafka,
Fang Zhang, Michael S. Kapiloff, and John D. Scott. Spatial restrictions
of PDK1 activation cascades by anchoring to mAKAPalpha. 2005, Mol Cell,
20:661-72.
Genevieve C. Pare, Andrea L. Bauman, Molly McHenry, Jennifer J.
Carlisle Michel, Kimberly L. Dodge-Kafka, and Michael S. Kapiloff. The
mAKAP complex participates in the induction of cardiac hypertrophy by
adrenergic receptor signaling. 2005, J Cell Science, 118:5637-46.
Kimberly L. Dodge-Kafka, Joseph Soughayer, Genevieve C. Pare,
Jennifer J. Carlisle Michel, Lorene K. Langeberg, Michael S. Kapiloff
and John D. Scott. The protein kinase A anchoring protein mAKAP
co-ordinates two integrated cAMP effector pathways. 2005, Nature,
437:574-578
Kimberly L. Dodge-Kafka*, Jennifer Michel Carlisle*, Ian Townley, and
John D. Scott. Serine 13 on PDE4D3 increases the binding and affinity
for the anchoring protein mAKAP. 2004, Biochem J, 381:587-592.
*Co-first Author
Kimberly L. Dodge*, Mark Dell'Aqua*, Steven J. Tavalin and John D.
Scott. Amino Acids 320-360 of AKAP79 are responsible for calcineurin
binding. 2002, Journal of Biological Chemistry 277:48796-802.
*Co-first Author
Kimberly L. Dodge, Samone Khouangsathiene, Michael S. Kapiloff,
Robert Mouton, Elaine V. Hill, Miles D. Houslay, Lorene K. Langeberg,
and John D. Scott. mAKAP asssembles a protein kinase A/PDE4
phosphodidesterase cAMP signaling module. 2001, EMBO 21:1921-30. |
