Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 131

of TGF b signaling depends on the interaction with arrestin3. 101 In vitro evi-
dence suggests that arrestin3 plays a key role in the ability of T b RIII to
inhibit cell migration. In breast and ovarian cancer cell lines, activation of
the small GTPase Cdc42 by T b RIII alters actin cytoskeletal rearrangement
and reduces random cell migration. 102 AT b RIII mutant unable to interact
with arrestins fails to inhibit migration and the wild-type receptor effect is
blocked by downregulating arrestin3. In addition, the interaction between
T b RIII and arrestin3 negatively regulates NF- k B transcriptional activity,
further inhibiting cell migration. 103

4.3.2 Casein kinase 2
Casein kinase 2 (CK2) is a ubiquitously expressed, constitutively active
Ser/Thr protein kinase that performs diverse functions related to cell survival
and tumorigenesis. The catalytic subunit of CK2 was identified in a proteo-
mic screen of arrestin3 binding proteins as well as a phosphoproteomic screen
of AT 1A receptor-mediated phosphorylation following stimulation with the
arrestin-selective biased agonist, SII. 51,58 Since CK2 has been implicated in
phosphorylation of Thr 383 of arrestin3, which destabilizes the interaction
between arrestin3 and b 2-adrenergic receptors, 104 it is possible that arrestin
recruitment of CK2 plays a role similar to that proposed for ERK1/2-
mediated phosphorylation of arrestin2 Ser 412 .

4.4. Protein phosphatases
4.4.1 PP2A - AKT - GSK3 b

The Ser/Thr phosphatase PP2A is ubiquitously expressed and has broad sub-
strate specificity. The PP2A holoenzyme is heterotrimeric, composed of reg-
ulatory A and B subunits that target the catalytic C subunit to specific
intracellular locations. The PP2A catalytic subunit was identified as an
arrestin3-interacting protein in a proteomic screen, 51 and a native
arrestin3-PP2A-AKT-GSK3 b complex has been purified from the D2 dopa-
mine receptor-rich striatum of mice. 23 The regulation of PP2A-AKT-GSK3
signaling by arrestins is probably one of the most physiologically important
arrestin-regulated signaling processes, being critically involved in both
AKT-dependent survival signaling and regulation of b -catenin-mediated
transcription. As previously discussed, the major homeostatic function of
the complex in the striatum is to modulate D2 dopamine receptor-mediated
behaviors by tonic repression of b -catenin signaling. 23,57 At the same time,
AT 1A receptor-mediated, G protein-independent, phosphorylation of the
PP2A inhibitor, I2PP2A, may provide a mechanism for acute modulation