The human body has evolved mechanisms to detect pathogenic organisms and to initiate an appropriate initial immune response against these organisms. Given the diversity of pathogens, a remarkable feature of these innate immunity-signaling pathways is their ability to tailor a response to a particular pathogen. Innate immune responses are initiated at the cell membrane by a family of receptors collectively termed the Toll-like Receptors (TLRs). Downstream signaling pathways activated by the TLRs include the ERK, JNK, p38 and NF- Kappabeta signaling modules. Activation of these signaling pathways then causes cytokine and chemokine release. There is a remarkable specificity to this immune response such that the cytokines released are tailored to the pathogen destined to be eradicated. Although critical, this specificity in signal transduction is poorly understood. The adapter protein kinase RIP2 may mediate a portion of this specificity. RIP2 has been shown to be involved in the proximal TLR signaling pathway as RIP2-null mice show defects in ERK, JNK, p38 and NF-kappaB signaling and subsequent deficiencies in cytokine release in response to LPS from gram-negative bacteria and PGN from gram-positive bacteria. Although RIP2 contains a serine-threonine kinase domain and it readily autophosphorylates, no in vivo RIP2 substrates have been identified. In preliminary studies, we have began to identify the preferred peptide phosphorylation sequence of RIP2. This initial data was used to help identify the adapter protein, TRAF6, as a phosphorylation substrate of RIP2. The central hypothesis of this grant is that as an essential component of the TLR pathway, RIP2's kinase activity may underly the specificity seen in innate immune signaling pathways. This grant application aims to define the preferred peptide phosphorylation sites of RIP2, to map the phosphorylation site of TRAF6 and to identify the physiologic significance of RIP2's phosphorylation of TRAF6.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Allergy & Clinical Immunology-1 (AITC)
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Prograis, Lawrence J
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Brigham and Women's Hospital
United States
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