Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt signaling

Abstract

β-Arrestins (Arrb) participate in the regulation of multiple signaling pathways, including Wnt/β-catenin, the major actor in human colorectal cancer initiation. To better understand the roles of Arrb in intestinal tumorigenesis, a reverse genetic approach (Arrb −/− ) and in vivo siRNA treatment were used in Apc Δ14/+ mice. Mice with Arrb2 depletion (knockout and siRNA) developed only 33% of the tumors detected in their Arrb2-WT littermates, whereas Arrb1 depletion remained without significant effect. These remaining tumors grow normally and are essentially Arrb2-independent. Unsupervised hierarchical clustering analysis showed that they clustered with 25% of Apc Δ14/+ ;Arrb2 +/+ tumors. Genes overexpressed in this subset reflect a high interaction with the immune system, whereas those overexpressed in Arrb2-dependent tumors are predominantly involved in Wnt signaling, cell adhesion, migration, and extracellular matrix remodeling. The involvement of Arrb2 in intestinal tumor development via the regulation of the Wnt pathway is supported by ex vivo and in vitro experiments using either tumors from Apc Δ14/+ mice or murine Apc Min/+ cells. Indeed, Arrb2 siRNAs decreased the expression of Wnt target genes in cells isolated from 12 of 18 tumors from Apc Δ14/+ mice. In Apc Min/+ cells, Arrb2 siRNAs completely reversed the increased Wnt activity and colony formation in soft agar induced by Apc siRNA treatment, whereas they did not affect these parameters in basal conditions or in cells expressing constitutively active β-catenin. We demonstrate that Arrb2 is essential for the initiation and growth of intestinal tumors displaying elevated Wnt pathway activity and identify a previously unsuspected molecular heterogeneity among tumors induced by truncating Apc mutations.tumor initiation | carcinogenesis

Fulfilling the Promise of "Biased" G Protein–Coupled Receptor Agonism

“…2D). Adding credence to the analysis, the major functions identified are consistent with the in vitro characterization of (D-Trp 12 ,Tyr 34 )-bPTH(7-34) actions in primary calvarial osteoblasts (Gesty-Palmer et al, 2013) and data emerging from the cancer field suggesting that arrestins function as regulators of tumor cell proliferation, survival, and metastasis (Buchanan et al, 2006;Dasgupta et al, 2006;Moussa et al, 2008;Chun et al, 2009;Lakshmikanthan et al, 2009;Li et al, 2009;Rosanò et al, 2009;Liu et al, 2011;Bonnans et al, 2012;Fereshteh et al, 2012).…”

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

“…These data suggest that ARRB1, but not ARRB2, plays an essential role in inflammationinduced hepatocellular carcinogenesis. It was reported that ARRB2, but not ARRB1, is essential for the initiation and growth of intestinal tumours 37 . Thus far, ARRB1 and ARRB2 have been found to have different effects in initiation and development of malignant tumours 23 .…”

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

“…Of note, a previous report determined that DVL2 loss protects against tumor development by reducing Wnt signaling in Apc min/+ ; Dvl2 ΔIEC mice (51), suggesting a nonredundant function of DVL2 for tumorigenesis in Apc min/+ mice. In addition, we noticed that several Wnt regulators, including WNK2, LKB1, β-arrestin 2, and RAF1, were altered in the absence of SETD2 (52)(53)(54)(55). For instance, β-arrestin 2 is essential for the initiation and growth of intestinal tumors displaying elevated Wnt pathway activity in Apc-mutated mice (54), and WNK2 also stimulates the Wnt signal through regulation of β-catenin stability (52).…”

“…In addition, we noticed that several Wnt regulators, including WNK2, LKB1, β-arrestin 2, and RAF1, were altered in the absence of SETD2 (52)(53)(54)(55). For instance, β-arrestin 2 is essential for the initiation and growth of intestinal tumors displaying elevated Wnt pathway activity in Apc-mutated mice (54), and WNK2 also stimulates the Wnt signal through regulation of β-catenin stability (52). Thus, we cannot completely rule out the possibility that, in addition to our findings, SETD2 might also act on different Wnt pathway components to finetune Wnt signals during intestinal regeneration and tumorigenesis.…”