Hello. I'm Michael Yaffe from the MIT Center for
Cancer Research and the Departments of Biology and Biological Engineering.
And the title of my talk is "Phosphoserine and
Phosphothreonine Binding Domains Molecular Integrators of Protein Kinase
Signaling in Cell Cycle Control and Cancer".
What I'd like to tell you about is how
phosphoserine and phosphothreonine binding domains are involved in
orchestrating cells signaling with a particular focus on
cell cycle control and the response to cells to DNA damage.
It's well established that in response to various types of stimuli,
such as growth factor stimulation or DNA damage,
protein kinase has become activated in cells and phosphorylate,
a subset of proteins within the cell
and these phosphorylated substrates then are believed to be
responsible for many of the molecular effects that follow after the initial stimulus.
Some of these molecular effects include things like cell cycle checkpoints,
DNA damage repair, or the decision of a cell to undergo
apoptosis or withdraw from the cell cycle and senensence.
There is also integration of the cell cycle and the DNA damage checkpoint pathways
so that it appears not only due to
cell cycle checkpoints inactivate progression through the cell cycle,
but progression through the cell cycle may be
required in order to activate DNA damage checkpoints.
The unique aspect of our approach to this problem has been making the claim that
phosphorylation of substrates by protein kinases alone may
not be enough to elicit the particular molecular effects that are observed.
Instead, it appears to be the interaction of
the phosphorylated substrates with specific phosphoserine,
phosphothreonine or phosphotyrosine-binding domains that
coordinates the action of the protein kinase with the molecular effect that we observe.
Therefore, it becomes important for us to not only
identify the phosphopeptide-binding domains and their substrates,
but to also use systems biology approaches to understand
the activation of different protein kinases as a function of time,
in order to understand how signalling networks are coordinated in time and space.
It's well established that protein phosphorylation