Biology Reference
In-Depth Information
primary vascular smooth muscle, a feature that probably contributes to
arrestin-dependent neointimal hyperplasia. 77 Arrestin signaling may also
protect cardiomyocytes from undergoing apoptosis. In vitro , a mutant b 1
adrenergic receptor that
lacks
the GRK phosphorylation sites
in its
C-terminal tail (-GRK
1) and cannot undergo arrestin-dependent desensi-
tization, fails to transactivate the EGF receptors despite exaggerated
G protein activation. 79 In response to chronic isoproterenol stimulation,
transgenic mice expressing the -GRK
b
1 receptor develop more severe
dilated cardiomyopathy with significantly increased LV end-diastolic
dimension, decreased fractional shortening, and increased myocardial apo-
ptosis, than wild-type
b
1 receptor transgenic mice, suggesting that arrestin
coupling promotes cardiomyocyte survival.
b
4.5. Cell migration, chemotaxis, and secretory function
Extensive data support the role of arrestin scaffolds in cytoskeletal
rearrangement and biological processes that depend on it, including vesicle
endocytosis, exocytosis, chemotaxis, migration, and metastasis (see Chapters
4 , 8 , 14 , and 15 ). Arrestins regulate several small G proteins involved in ves-
icle trafficking and cytoskeletal reorganization; including RalA/B; the Rho
family GTPases Rho, Rac, and Cdc42; several Rab isoforms; and ARF6 (see
Chapter 6 ). Arrestin scaffolding of Src family nonreceptor tyrosine kinases
regulates GRK2, dynamin, and adaptor protein (AP)2 function during
GPCR endocytosis, 80-84 and plays a role in secretory granule release and
exocytic vesicle-dependent translocation of the glucose transporter,
Glut4. 85,86 Arrestin-dependent regulation of ERK1/2 and cortical actin
assembly at the leading edge is required for GPCR-mediated chemotaxis.
During protease-activated receptor (PAR2) stimulated chemotaxis, assem-
bly of a PAR2-arrestin-ERK1/2 complex at the leading edge activates actin
cytoskeleton reorganization. 87,88 In addition, arrestins scaffold a GPCR-
based complex containing the actin filament-severing protein, cofilin,
LIM kinase, and the cofilin-specific phosphatase, chronophin, which is
required for the dephosphorylation and activation of cophillin. 89
Arrestin-bound cophillin generates the free barbed ends on actin filaments
that permit filament extension.
In addition to its roles in promoting cancer cell proliferation and survival,
arrestin-dependent cell migration may contribute to invasive cancer pheno-
types. As mentioned previously, arrestin signaling by the TP-
receptor pro-
motes cell migration and invasion in vitro , responses that are lost when
b
Search WWH ::




Custom Search