Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.
Repository Usage Stats
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.
Zinc Finger Protein GLI1
beta-Adrenergic Receptor Kinases
Published Version (Please cite this version)10.1128/MCB.00546-06
Publication InfoMeloni, Alison R; Fralish, Gregory B; Kelly, Patrick; Salahpour, Ali; Chen, James K; Wechsler-Reya, Robert J; ... Caron, Marc G (2006). Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol, 26(20). pp. 7550-7560. 10.1128/MCB.00546-06. Retrieved from https://hdl.handle.net/10161/7792.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
More InfoShow full item record
James B. Duke Distinguished Professor of Cell Biology
Studies of the mechanisms of action and regulation of hormones and neurotransmitters at the cellular and molecular levels constitute the main goals our of research activities. G protein-coupled receptors (GPCR) mediate the actions of signaling molecules from unicellular organisms to man. We have used adrenergic and dopamine receptors to characterize the structure/function and regulation mechanisms of these prototypes of G protein-coupled receptors. Another approach has been to characterize
James B. Duke Distinguished Professor of Medicine
The focus of work in this laboratory is on the elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. As model systems we utilize the so called adrenergic receptors for adrenaline and related molecules. The goal is to learn the general principles of signal transduction from the outside to the inside of the cell which are involved in systems as diverse as sensory perception, neuro- transmitter and hormonal signaling. Stud
Adjunct Associate Professor in the Department of Pharmacology & Cancer Biology
Our research focuses on the molecular mechanisms that regulate cell growth and tumorigenesis in the nervous system. In particular, we study the role of the Sonic hedgehog (Shh) signaling pathway in the development of the cerebellum and in the genesis of a brain tumor called medulloblastoma. Sonic hedgehog is a secreted signaling molecule that plays a critical role in regulating many aspects of development. In the cerebellum, Shh acts as a potent mitogen for neurons called gran
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Alphabetical list of authors with Scholars@Duke profiles.
Showing items related by title, author, creator, and subject.
LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT. Kaufman, Jacob M; Amann, Joseph M; Park, Kyungho; Arasada, Rajeswara Rao; Li, Haotian; Shyr, Yu; Carbone, David P (Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2014-06)Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene ...
Amino acid permeases require COPII components and the ER resident membrane protein Shr3p for packaging into transport vesicles in vitro. Kuehn, MJ; Schekman, R; Ljungdahl, PO (J Cell Biol, 1996-11)In S. cerevisiae lacking SHR3, amino acid permeases specifically accumulate in membranes of the endoplasmic reticulum (ER) and fail to be transported to the plasma membrane. We examined the requirements of transport of the ...
Touhara, K; Hawes, BE; van Biesen, T; Lefkowitz, RJ (Proc Natl Acad Sci U S A, 1995-09-26)The mechanism of mitogen-activated protein (MAP) kinase activation by pertussis toxin-sensitive Gi-coupled receptors is known to involve the beta gamma subunits of heterotrimeric G proteins (G beta gamma), p21ras activation, ...