Mechanism of ERK activation and its function in
T and NK cell function

We are interested in the mechanisms that control ERK activation during T and NK cell activation.  How ERK is activated and what it does is not known. This problem is complicated by multiple Ras isoforms expressed in cells, their differential localization and many different exchange factors capable of activating Ras.  In addition, scaffolding proteins play an important role in organizing the MAP kinase signaling pathway in cells.  We are interested in understanding how the MAP kinase ERK is activated during T cell activation and what its specific function is.

  1. What is the role of the MAP kinase scaffolds, KSR1 and KSR2 in T cell activation? Kinase suppressor of Ras (KSR) was originally identified in fly and worm as genes important in the Ras/ERK signaling pathway. The current model is that KSR which is a pseudokinase functions as a scaffold and binds to Raf, MEK and ERK. We showed that KSR1 deficient T cells have impaired T cell activation. Our current work focuses on analysis of the KSR1 and KSR2 deficient mice, their patterns of expression and their roles in immune physiology.
  2. What is the role of ERK recruitment to the immunological synapse? Several groups have now reported that ERK is recruited to the immunological synapse during T cell activation. We are interested to know what the substrates for ERK are at the synapse, what function ERK phosphorylation plays and the mechanism of ERK recruitment to the synapse instead of ERK translocation to the nucleus.
  3. How does ERK translocate to the synapse? What determines whether ERK goes to the plasma membrane or goes to the nucleus?