Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice.
Abstract
Lymphocyte chemotaxis is a complex process by which cells move within tissues and
across barriers such as vascular endothelium and is usually stimulated by chemokines
such as stromal cell-derived factor-1 (CXCL12) acting via G protein-coupled receptors.
Because members of this receptor family are regulated ("desensitized") by G protein-coupled
receptor kinase (GRK)-mediated receptor phosphorylation and beta-arrestin binding,
we examined signaling and chemotactic responses in splenocytes derived from knockout
mice deficient in various beta-arrestins and GRKs, with the expectation that these
responses might be enhanced. Knockouts of beta-arrestin2, GRK5, and GRK6 were examined
because all three proteins are expressed at high levels in purified mouse CD3+ T and
B220+ B splenocytes. CXCL12 stimulation of membrane GTPase activity was unaffected
in splenocytes derived from GRK5-deficient mice but was increased in splenocytes from
the beta-arrestin2- and GRK6-deficient animals. Surprisingly, however, both T and
B cells from beta-arrestin2-deficient animals and T cells from GRK6-deficient animals
were strikingly impaired in their ability to respond to CXCL12 both in transwell migration
assays and in transendothelial migration assays. Chemotactic responses of lymphocytes
from GRK5-deficient mice were unaffected. Thus, these results indicate that beta-arrestin2
and GRK6 actually play positive regulatory roles in mediating the chemotactic responses
of T and B lymphocytes to CXCL12.
Type
Journal articleSubject
AnimalsArrestins
Chemotaxis, Leukocyte
Crosses, Genetic
G-Protein-Coupled Receptor Kinase 5
G-Protein-Coupled Receptor Kinases
GTP-Binding Proteins
Gene Expression Regulation
Kinetics
Lymphocyte Subsets
Lymphocytes
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein-Serine-Threonine Kinases
beta-Arrestins
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https://hdl.handle.net/10161/7804Published Version (Please cite this version)
10.1073/pnas.112198299Publication Info
Fong, Alan M; Premont, Richard T; Richardson, Ricardo M; Yu, Yen-Rei A; Lefkowitz,
Robert J; & Patel, Dhavalkumar D (2002). Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proc Natl Acad Sci U S A, 99(11). pp. 7478-7483. 10.1073/pnas.112198299. Retrieved from https://hdl.handle.net/10161/7804.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.
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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 James B. Duke Professor of Medicine and Professor of
Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator
of the
Dhavalkumar Dhirajlal Patel
Associate Consulting Professor in the Department of Medicine
The overall goals of the Patel laboratory are two-fold: 1) to define the mechanisms
of inflammation, focusing on signaling through G protein coupled receptors, for the
purpose of identifying novel therapeutic targets for immunologic diseases; and 2)
to define the role that T cell education in the thymus plays in diseases of disordered
immunity such as autoimmune diseases and primary immunodeficiency syndromes. 1. Roles
of Membrane-Tethered Chemokines in Inflammation. Based on o
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
Yen-Rei Andrea Yu
Adjunct Assistant Professor in the Department of Medicine
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