In this study, we report on the isolation of a PDZ domain protein, here designated as IIP-1, insulin-like growth factor-1 (IGF-1) receptor-interacting protein-1, which binds to the IGF-1 receptor, but not to the related insulin receptor, and which is involved in the regulation of cell motility. Signaling by the insulin-like growth factor-1 (IGF-1) 1 receptor plays a crucial role in cellular growth, migration, and survival (1). The IGF-1 receptor belongs to the family of receptor tyrosine kinases and shares a high degree of homology with the insulin receptor (2). Several signaling proteins are known to interact with the cytoplasmic part of the IGF-1 receptor, the insulin receptor and several other receptor tyrosine kinases. For example, it was shown that p85, the regulatory domain of the PI3K, interacts with the IGF-1 receptor (3, 4). However, p85 also binds to many other receptor tyrosine kinases of virtually all sub-families. Another binding partner of the IGF-1 receptor defined by two-hybrid screening is Grb 10, which binds also to other receptor tyrosine kinases like the insulin receptor and c-Ret (5-7). IRS-1, IRS-2, and SHC were also found to interact both with the IGF-1 receptor and the insulin receptor (5,8,9). More recently, mSH2B was described as IGF-1 receptor binding protein, which also interacts with the insulin receptor (10). 14-3-3 proteins were shown to interact with the IGF-1 receptor but not the insulin receptor (11). However, 14-3-3 proteins also influence insulin signaling via binding to IRS-1 (12). Taken together, relatively little is known about specific signal transducers of the IGF-1 receptor.The primary physiological role of the insulin receptor is to regulate metabolic events, whereas the IGF-1 receptor activated by its ligands has a major impact on mitogenicity, transformation, and survival (13). In addition, signaling by the IGF-1 receptor is implicated in the chemotactic activity of tumor cells (14). Thus, despite the similarity of the amino acid sequence and many shared signaling proteins, unique biological effector molecules for the IGF-1 receptor and the insulin receptor are likely to participate in transducing the specific responses of these receptors. The finding that signaling of receptor chimera, in which the cytoplasmic domain of the IGF-1 receptor was fused to the extracellular domain of the insulin receptor, caused an increased mitogenic response compared with the wild type insulin receptor, supports the hypothesis of such divergent pathways (15). The C-terminal region represents the most disparate domain between the IGF-1 receptor and the insulin receptor and is particularly important for the differences in signaling events (16 -20). Thus, this region might act as a prime candidate binding site for specific signaling proteins. The knowledge of such specific protein interactions discriminating the IGF-1 receptor from the insulin receptor might open novel ways for targeted therapeutic interventions.To elucidate the differences in the signal transduction pathways of the IGF-1 ...
The Enhancer of split gene complex [E(spl)-C] of Drosophila melanogaster harbors seven highly related genes encoding transcriptional regulators with a basic helix-loop-helix (bHLH) domain. They are activated by the Notch signaling pathway in order to inhibit proneural gene activity, for example, during neurogenesis in the developing embryo. The E(spl) proteins are at least partly redundant, despite some remarkable differences in their expression patterns. We attempted to address the degree of redundancy by means of RNA interference. We find a quantitative correlation between the degree of a neurogenic phenotype and the number of genes affected. Surprisingly, interference with m3 results in a high rate of mortality which cannot be reproduced by genetic mutation. Most likely, m3 dsRNA interferes with unrelated genes involved in other aspects of embryonic development.
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