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b -arrestin2 does not diminish IGF-1R ubiquitination. The b -arrestin
homolog Kurtz expressed in Drosophila also acts as an E3 ligase adaptor. 83
Kurtz binds to both the Notch receptor and the HECT domain E3 ligase
Deltex and mediates Notch ubiquitination and downregulation. 83
b -Arrestin2 forms a complex with the androgen receptor (AR) and acts
as an AR corepressor in androgen-dependent prostate cancer cells by pro-
moting Mdm2-dependent ubiquitination and degradation of AR. 84
4.3. Ion channels
An adaptor role of b -arrestin1 has recently been discovered for transient
receptor potential (TRP) ion channel family member TRPV4 and Na þ /
H þ exchanger 1 (NHE1) ubiquitination, in which the E3 ligases AIP4
and Nedd4-1 are involved, respectively. 85,86 TRPV4 is widely expressed
in various tissues and initiates Ca 2 þ influx upon activation. Interestingly,
TRPV4 and AT 1a R are found to coexist as complexes at the plasma mem-
brane. 85 Upon AT 1a R activation, b -arrestin1 is recruited to this complex
resulting in the internalization of TRPV4 and inhibition of Ca 2 þ influx into
cells. This functional downregulation requires ubiquitination of TRPV4
mediated by AIP4 which is escorted specifically by b -arrestin1. 85 NHE1
is expressed ubiquitously and controls cell volume and pH; protein turnover
of this ion transport protein requires ubiquitination of the intracellular
domain by Nedd4 which is recruited in a b -arrestin1-dependent manner. 86
Because NHE1 shares homology with other 11 members of this protein
family and internalization of NHE5 is mediated by b -arrestins, it is tempting
to speculate that b -arrestin-dependent ubiquitination would be a common
theme in the regulation of these ion-transport proteins. 87
4.4. Enzymes and other proteins
Ubiquitination of GRK2 is triggered by b 2 AR stimulation and is mediated
by Mdm2. 88,89 Association between GRK2 and Mdm2 is augmented upon
agonist activation of b 2 ARs and is regulated by phosphorylation on GRK2
at Serine 670 by MAPKs. Under agonist-induced conditions, b -arrestin1
and/or b -arrestin2 scaffolded Mdm2 ubiquitinates GRK2 and promotes
its degradation via 26S proteasomes. Interestingly, b -arrestins also facilitate
an alternative mode of degradation that is augmented when c-Src tyrosine
phosphorylates GRK2, an event that occurs independent of Mdm2 under
basal or agonist-independent conditions. 88 Thus for GRK2, b -arrestins
can scaffold multiple E3 ligases, suiting the signaling context prevalent in
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