Identification and Characterization of a PDZ Protein That Interacts with Activin Type II Receptors

Abstract

We have identified a mouse PDZ protein that interacts with the activin type IIA receptor (ActRIIA), which we named activin receptor-interacting protein 1 (ARIP1). By using yeast two-hybrid screening, we isolated a cDNA clone of ARIP1 from a mouse brain cDNA library. We detected two forms of ARIP1, ARIP1-long and ARIP1-short, which may be produced by alternative splicing. ARIP1-long had one guanylate kinase domain in the NH 2 -terminal region, followed by two WW domains and five PDZ domains (PDZ1-5). ARIP1-short had a deletion in the NH 2 -terminal region and lacked the guanylate kinase domain. Both forms interacted with ActRIIA through PDZ5. The COOH-terminal residues of ActRIIA (ESSL) agree with a PDZ-binding consensus motif, and ARIP1 recognized the consensus sequence. ARIP1 interacts specifically with ActRIIA among the receptors for the transforming growth factor ␤ family. Interestingly, ARIP1 also interacted with Smad3, which is an activin/ transforming growth factor ␤ intracellular signaling molecule. The mRNA of ARIP1 was more abundant in the brain than in other tissues. Overexpression of ARIP1 controls activin-induced and Smad3-induced transcription in activin-responsive cell lines. These findings suggest that ARIP1 has a significant role in assembling activin signaling molecules at specific subcellular sites and in regulating signal transduction in neuronal cells.

Endocytic regulation of TGF-β signaling

“…RalBP1 has been shown, as an effector of the GTPase Ral, to regulate endocytosis of epidermal growth factor and insulin receptors [114]. Interestingly, unlike ARIP2, which contains only one PDZ domain, ARIP1, which has five PDZ domains and two WW domains, was reported to promote activin signaling by acting as a scaffold protein to bring ActRIIA and Smad3 proteins together [115].…”

MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap

“…Consistent with this, the MAGI-3 clone only interacted with frizzled-4 and -7 as measured by the ability of yeast to grow in nutrient depleted (His-) media and by expression of b-galactosidase. MAGI-3 is a member of the MAGUK family and two closely related family members, BAP1/MAGI-1 and S-SCAM/AIP1/ ARIP1/MAGI-2, have been described (Dobrosotskaya et al, 1997;Hirao et al, 1998;Shiratsuchi et al, 1998;Wood et al, 1998;Shoji et al, 2000). Like these family members, MAGI-3 contains six PDZ domains (PDZ0-PDZ5), one guanylate kinase (GK) domain, and two WW domains (Wu et al, 2000;Adamsky et al, 2003).…”

Activin increases the number of synaptic contacts and the length of dendritic spine necks by modulating spinal actin dynamics

“…Phosphorylated Smad2/Smad3 subsequently interacts with Smad4 and the resulting complex translocates to the nucleus to activate target gene expression. The ActRII-binding PDZ protein, Arip-1 (also known as S-scam and Magi2), localizes at the synaptic site of hippocampal neurons (Shoji et al, 2000). In addition, other Smad-independent pathways are also activated by activin receptors, including MAP kinase signaling routes (ten Dijke et al, 2000;Werner and Alzheimer, 2006).…”