The catenin proteins contribute to the biology of all animal cells and tissues, displaying essential embryonic and adult functions within a variety of sub-cellular compartments. In addition to binding cadherin at the plasma membrane, B- catenin is well known to associate in the nucleus with transcription factors of the TCF/LEF family in transducing developmental Wnt signals crucial to development, for example, dorsal axis formation, limb patterning and neurogenesis. More recently, the ARVCF and p120 catenins have gained notice in the context of cadherin function at the plasma membrane and other potential roles within the nucleus. Perhaps the most prominent finding was that p120 modulates Rho-family GTPases crucial to cell motility and adhesion. As will be made evident, we have likewise accumulated evidence that ARVCF is functionally coupled to RhoA, and outline in this Proposal our plans to address the developmental role of ARVCF (and p120) in modulating Rho-family GTPases. To gain further insight of ARVCF function, we have conducted yeast two-hybrid screens for interacting protein partners. We recently identified three novel protein associations that were authenticated using in vitro and in vivo co precipitation approaches. We term these three proteins CAPs (Catenin Associated Protein), and expect that the physical association of each CAP reflects a distinct functional interaction which we propose to examine in the context of this Proposal. For our studies, we will employ the Xenopus embryo system that allows for the facile introduction (injection) of exogenous constructs/reagents and the rapid development of this vertebrate within an external environment. We will conduct experiments largely based upon loss-of-function (morpholino), exogenous expression and rescue approaches.
Aims Addressed 1. What functional relationship exists between ARVCF (and Xp120) and each CAP? 2. What functional relationship exists between ARVCF (and p120) and Rho-family GTPases? Hypotheses Tested 1. CAPs modulate ARVCF (and p120) developmental functions 2. ARVCF (and p120) modulate the developmental functions of Rho-family GTPases
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