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REGIONAL CENTRE FOR BIOTECHNOLOGY
cAMP dependent protein kinase A (PKA): New insights from
an old kinase
Malik Keshwani, PhD
HHMI, University of California, San Diego
Monday, 4th, March, 2013
REGIONAL CENTRE FOR BIOTECHNOLOGY
cAMP-dependent protein kinase A (PKA) is ubiquitously expressed in mammalian cells and regulates various
cellular processes including transcription, metabolism, apoptosis and ion channel regulation. PKA exist as an
inactive tetrameric holoenzyme constituting regulatory subunit dimer and two catalytic subunits. The Regulatory
subunit (PKA-R) binds two molecules of cAMP and unleashes catalytic subunit (PKA-C) which then carries out
phosphorylation of various protein targets. The PKA-C is constitutively active and has two phosphorylation sites, a
well-studied site in the activation loop (Thr197) and another site in the C-terminal tail (Ser338) for which the role of
phosphorylation is unknown. Using in vitro and cell culture studies, we show that cis-autophosphorylation of Ser338
occurs cotranslationally, when PKA-C is associated with ribosomes and precedes posttranslational
phosphorylation of the activation loop Thr197. Ser338 phoshorylation is not required for PKA-C activity or formation
of the holoenzyme complex; however, it is critical for processing and maturation of PKA-C, and it is a prerequisite
for phosphorylation of Thr197. Once Thr197 and Ser338 are phosphorylated, both sites are remarkably resistant to
phosphatases. Using S49 kin minus cell lines that resist cAMP mediated apoptosis and have no solube PKA-C, we
show that PKA-C is not phosphorylated at Ser338 and as a consequence completely insoluble and inactive.
Furthermore, there is significant reduction of PKA-R1
α), which is required for pro-apoptotic Bim-caspase
mediated apoptosis on cAMP treatment. We also show that kin minus cells undergo apoptosis on Dexamethasone
treatment via caspase independent Apoptosis inducing factor pathway whereas the wild type S49 cells uses Bim-
caspase pathway. We also show that cAMP inhibits Ser338 phosphorylation and leads to insolubility and improper
maturation of PKA-C and provide a mechanism for the apoptosis resistant phenotype of kin minus lymphoma cells.
We revisited role of metal ions in assisting phospho-transfer. Using PKA as a model kinase, with kinetics and
structural studies, we found that metal ion serve as electrostatic quenchers of negative charges of ATP so that ATP
can bind the negatively charged active site of protein kinase thus facilitating phospho-transfer. We also show that
all divalent metal ions assist in phospho-transfer reaction using two different protein kinases. Our data suggests
that metal ions do not affect the rate of phospho-transfer but instead just serves as carriers of ATP into and out of
the active site of protein kinase.
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ANNEXURE - 2 Ph.D. programme for the Academic year 2010-11 Sl. Name of the Student Program Title/ Topic Research Name & Academic Qualifications of the Research Research Supervisor is a Supervisor permanent/ad- hoc/temporary / visiting Histopathological Evaluation of Implanted Autologous Crushed and Noncrushed Auricular Cartilate Graft with i