Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling

Abstract

Activin type II receptors (ActRIIs) including ActRIIA and ActRIIB are serine/threonine kinase receptors that form complexes with type I receptors to transmit intracellular signaling of activins, nodal, myostatin and a subset of bone morphogenetic proteins. ActRIIs are unique among serine/threonine kinase receptors in that they associate with proteins having PSD-95, Discs large and ZO-1 (PDZ) domains. In our previous studies, we reported specific interactions of ActRIIs with two independent PDZ proteins named activin receptor-interacting proteins 1 and 2 (ARIP1 and ARIP2). Overexpression of both ARIP1 and ARIP2 reduce activin-induced transcription. Here, we report the isolation of two isoforms of ARIP2 named ARIP2b and 2c. ARIP2, ARIP2b and ARIP2c recognize COOH-terminal residues of ActRIIA that match a PDZ-binding consensus motif. ARIP2 and its isoforms have one PDZ domain in the NH 2 -terminal region, and interact with ActRIIA. Although PDZ domains containing GLGF motifs of ARIP2b and 2c are identical to that of ARIP2, their COOH-terminal sequences differ from that of ARIP2. Interestingly, unlike ARIP2, overexpression of ARIP2b or 2c did not affect ActRIIA internalization. ARIP2b/2c inhibit inhibitory actions of ARIP2 on activin signaling. ARIP2 is widely distributed in mouse tissues. ARIP2b/2c is expressed in more restricted tissues such as heart, brain, kidneys and liver. Our results indicate that although both ARIP2 and ARIP2b/2c interact with activin receptors, they regulate ActRIIA function in a different manner.

Molecular characterization of Activin Receptor Type IIA and its expression during gonadal maturation and growth stages in rohu carp

“…Although, it is apparent that these modifications regulate receptor functions, how regulation at these predicted sites are capable of maintaining the receptor stability and action will be thoroughly studied further. Besides PTMs, there are several other intracellular regulatory molecules like ARIPS (activin receptor-interacting proteins) that are found to associate with ActRIIA via PDZ-domain and mediate signaling machinery for activin (Tsuchida et al, 2001;Liu et al, 2006). The present results in accordance with earlier reports suggest that the PDZ-motif "E-S-S-L" identified at the COOH-terminus of ActRIIA sequence might be involved in interaction with ARIPS for receptor internalization and endocytosis.…”

Activins and activin antagonists in hepatocellular carcinoma

“…In contrast, elevated BAMBI expression driven by the Wnt/β-catenin pathway was found in HCC and CRC specimens [135] . ARIPS 1 and 2 (activin receptor-interacting proteins) are PDZ (PSD-95/Discs-large/ZO-1) protein-protein interaction domain-containing proteins that were described to interact with type Ⅱ activin receptors and inhibit or augment activin signaling, depending on the isoforms expressed [136][137][138] . ARIP 2 was recently shown to be induced by activin A in the mouse hepatoma cell line Hepa1-6 and to decrease activin-mediated collagen Ⅳ expression, suggesting that it participates in a negative feedback regulation of activin-induced liver fibrosis [139] .…”

Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV

“…ARIPs have obvious expression and distribution diversity, which are key factors to the histological specificity of activin action [6][7][8] . It has been demonstrated that both ARIP1 and ARIP2 are inhibitors of activin signal transduction.…”

“…The vector construction has been described previously [8] . The set of primers was designed as follows.…”

“…It has been found that the tissue-specificity might depend on a new group of intracellular signal proteins, activin receptor-interacting proteins (ARIPs) [6][7][8] . ARIPs have four forms at least, all of which can specifically interact with activin type Ⅱ receptor (ActRII) and regulate intracellular signal transduction induced by activin [6][7][8][9][10] . It has been demonstrated that not only the expression and distribution but also the biological activities of ARIPs were obviously different in various tissues.…”