Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.

Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of the transcription factor Gli. The activity of mammalian Smoothened is controlled by three different hedgehog proteins, Indian, Desert, and Sonic hedgehog, through their interaction with the Smoothened inhibitor Patched. However, the mechanisms of signal transduction from Smoothened are poorly understood. We show that a kinase which regulates signaling by many "conventional" 7TM G-protein-coupled receptors, G protein-coupled receptor kinase 2 (GRK2), participates in Smoothened signaling. Expression of GRK2, but not catalytically inactive GRK2, synergizes with active Smoothened to mediate Gli-dependent transcription. Moreover, knockdown of endogenous GRK2 by short hairpin RNA (shRNA) significantly reduces signaling in response to the Smoothened agonist SAG and also inhibits signaling induced by an oncogenic Smoothened mutant, Smo M2. We find that GRK2 promotes the association between active Smoothened and beta-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by beta-arrestin 2 knockdown with shRNA. Together, these data suggest that GRK2 plays a positive role in Smoothened signaling, at least in part, through the promotion of an association between beta-arrestin 2 and Smoothened.

Furnishing a Globalized World: Local Distinctiveness in the International Furniture Industry

Advances in technology, communication, and transportation over the past thirty years have led to tighter linkages and enhanced collaboration across traditional borders between nations, institutions, and cultures. This thesis uses the furniture industry as a lens to examine the impacts of globalization on individual countries and companies as they interact on an international scale. Using global value chain analysis and international trade data, I break down the furniture production process and explore how countries have specialized in particular stages of production to differentiate themselves from competitors and maximize the benefits of global involvement. Through interviews with company representatives and evaluation of branding strategies such as advertisements, webpages, and partnerships, I investigate across four country cases how furniture companies construct strong brands in an effort to stand out as unique to consumers with access to products made around the globe. Branding often serves to highlight distinctiveness and associate companies with national identities, thus revealing that in today’s globalized and interconnected society, local differences and diversity are more significant than ever.