ABSTRACT
The oncoprotein Smoothened (SMO), a Frizzled-class-G-protein-coupled receptor, is the central transducer of hedgehog (Hh) signaling. While canonical SMO signaling is best understood in the context of cilia, evidence suggests that SMO has other functions in cancer biology that are unrelated to canonical Hh signaling. Herein, we provided evidence that elevated levels of human SMO show a strong correlation with elevated levels of insulin-like growth factor 1 receptor (IGF1R) and reduced survival in diffuse large B-cell lymphoma (DLBCL). As an integral component of raft microdomains, SMO plays a fundamental role in maintaining the levels of IGF1R in lymphoma and breast cancer cells as well IGF1R-associated activation of protein kinase B (AKT). Silencing of SMO increases lysosomal degradation and favors a localization of IGF1R to late endosomal compartments instead of early endosomal compartments from which much of the receptor would normally recycle. In addition, loss of SMO interferes with the lipid raft localization and retention of the remaining IGF1R and AKT, thereby disrupting the primary signaling context for IGF1R/AKT. This activity of SMO is independent of its canonical signaling and represents a novel and clinically relevant contribution to signaling by the highly oncogenic IGF1R/AKT signaling axis.
Subject(s)
Insulin-Like Growth Factor I , Proto-Oncogene Proteins c-akt , Hedgehog Proteins/metabolism , Humans , Proto-Oncogene Proteins c-akt/metabolism , Receptor, IGF Type 1/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal Transduction/physiology , Smoothened Receptor/metabolismABSTRACT
The present study evaluated the emergence of second-language intraverbals in typically developing young children following a small-group teaching intervention. Choral responding was employed with a group of 6 primary school children (5-6 years old) to teach first-language tacts (e.g., "What is this in English?" ["Hospital"]) and related second-language tacts (e.g., "What is this in Welsh?" ["Ysbyty"]). A multiple-probe design across stimulus sets was used to evaluate subsequent emergence of untrained first-to-second-language derived intraverbals (e.g., "What is hospital in Welsh?" ["Ysbyty"]) and untrained second-to-first-language intraverbals (e.g.,"What is ysbyty in English?" ["Hospital"]). Data indicated that the choral responding intervention produced robust increases in derived intraverbal relations for 3 of the 6 participants.
