Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity.
Abstract
Recently, we identified a GTPase-activating protein for the ADP ribosylation factor
family of small GTP-binding proteins that we call GIT1. This protein initially was
identified as an interacting partner for the G protein-coupled receptor kinases, and
its overexpression was found to affect signaling and internalization of the prototypical
beta(2)-adrenergic receptor. Here, we report that GIT1 overexpression regulates internalization
of numerous, but not all, G protein-coupled receptors. The specificity of the GIT1
effect is not related to the type of G protein to which a receptor couples, but rather
to the endocytic route it uses. GIT1 only affects the function of G protein-coupled
receptors that are internalized through the clathrin-coated pit pathway in a beta-arrestin-
and dynamin-sensitive manner. Furthermore, the GIT1 effect is not limited to G protein-coupled
receptors because overexpression of this protein also affects internalization of the
epidermal growth factor receptor. However, constitutive agonist-independent internalization
is not regulated by GIT1, because transferrin uptake is not affected by GIT1 overexpression.
Thus, GIT1 is a protein involved in regulating the function of signaling receptors
internalized through the clathrin pathway and can be used as a diagnostic tool for
defining the endocytic pathway of a receptor.
Type
Journal articleSubject
Adaptor Proteins, Signal TransducingAnimals
COS Cells
Cell Cycle Proteins
Cells, Cultured
Cercopithecus aethiops
Cyclic AMP
Endocytosis
GTP-Binding Proteins
GTPase-Activating Proteins
Humans
Phosphoproteins
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
Receptor, Endothelin B
Receptors, Adrenergic, beta
Receptors, Angiotensin
Receptors, Cell Surface
Receptors, Endothelin
Receptors, Muscarinic
Receptors, Opioid, mu
Receptors, Vasoactive Intestinal Peptide
Recombinant Fusion Proteins
Transfection
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Show full item recordScholars@Duke
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee
Richard Thomas Premont
Associate Professor in Medicine
Critical physiological events throughout the body are controlled by extracellular
signals from neurotransmitters and hormones acting on cell surface receptors. Receptors
transduce these signals to alter intracellular metabolism and cellular responsiveness
through heterotrimeric G protein/second messenger pathways or through small GTP-binding
protein/protein kinase cascades. The mechanisms that control the responsiveness of
target organ G protein-coupled receptors include receptor ph
Julia K.L. Walker
Helene Fuld Health Trust Distinguished Professor of Nursing
Broadly, my research focuses on the role for G protein-coupled receptors in the pathophysiology
of asthma. Asthma is a complex disease characterized by airway inflammation, hyperresponsiveness
and remodeling. G protein-coupled receptors figure largely in the pathology and treatment
of this disease. For example, beta-agonists, the rescue medication inhaled by asthmatics,
act at airway smooth muscle beta2-adrenergic receptors (β2-AR) to relax the airways.
However, excessive use of beta-a
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