The Tumor Necrosis Factor Receptor Associated Factor, or TRAF family of adaptor proteins relays signals from cytokine receptors to downstream signal transducers to affect apoptosis, inflammation, immunity and cell differentiation. The TRAF family consists of six distinct proteins, TRAFs 1-6, and most function in Tumor Necrosis Factor (TNF) and lnterleukin-1/Toll-related (IL/TLR) signal transduction pathways. One member of the family named TRAF4 does not function in TNF and IL/TLR signaling. TRAF4 biology and biochemistry is largely a mystery, however we have recently discovered that TRAF4 enhances signaling by the two major branches of the Transforming Growth Factor-beta superfamily, the BMP and TGF-beta/nodal pathways. TRAF4 appears to act at the signal transduction level, possibly by regulating the Smurf ubiquitin ligases or R-Smads. In developing embryos of the amphibian Xenopus laevis, misexpression or inhibition of TRAF4 disrupts development of the head, dorsal mesoderm and neural crest, revealing a critical function for TRAF4 in the development of these tissues. Recent protein interaction screens have yielded TRAF4 partners not implicated in TGFbeta signaling, but how these factors function in TRAF4 signal transduction and development is barely understood. The main objective of this grant is to understand how TRAF4 enhances TGF-beta or other signaling pathways in vertebrate development.
Aim 1 will tackle the mechanism of TRAF4 in BMP and nodal signaling by testing whether TRAF4 and TGF-beta signal transduction molecules interact, and by analyzing the biochemical effects of those interactions.
Aim 2 will test how TRAF4 regulates Xenopus embryonic development by ectopically expressing TRAF4 or blocking endogenous TRAF4. Emphasis will be on determining how TRAF4 regulates differentiation of the mesoderm, ectoderm and neural crest. TRAF4 also interacts with several proteins implicated in non-TGFbeta pathways.
Aim 3 will examine whether these proteins connect TRAF4 to upstream signals or function as downstream effectors in Xenopus development. TGFbeta pathways govern cell growth, differentiation, immunity and development. Understanding how TRAF4 regulates TGF-beta signaling or other pathways in vertebrate development will impact the fields of signal transduction and embryology and provide vital information for understanding how immune and inflammatory diseases, cancers and birth defects might arise from abnormal TGF-beta and TRAF signaling. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Haynes, Susan R
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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Callery, Elizabeth M; Thomsen, Gerald H; Smith, James C (2010) A divergent Tbx6-related gene and Tbx6 are both required for neural crest and intermediate mesoderm development in Xenopus. Dev Biol 340:75-87
Kalkan, Tuzer; Iwasaki, Yasuno; Park, Chong Yon et al. (2009) Tumor necrosis factor-receptor-associated factor-4 is a positive regulator of transforming growth factor-beta signaling that affects neural crest formation. Mol Biol Cell 20:3436-50
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