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. |
