Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Abstract

All major cell types in pancreatic islets express the transforming growth factor (TGF)-␤ superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in ␤-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca 2؉ signaling in islet cells, with activin A increasing, but activin B decreasing, glucosestimulated Ca 2؉ influx. On its own, activin B had no effect on WT cells, but stimulated Ca 2؉ influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7 ؊/؊ mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca 2؉ signaling in ␤-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting ␤-cell function by mediating the effects of activin B on Ca 2؉ signaling.T he signaling networks controlling metabolic processes are highly regulated and integrate the actions of both positively and negatively acting components from many different signaling pathways. Members of the transforming growth factor (TGF)-␤ superfamily, including TGF-␤s, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and activins, have been implicated in the regulation of several metabolic processes. These ligands signal via distinct complexes of type I and type II receptor serine-threonine kinases, each binding to different classes of TGF-␤ ligands (1, 2). The main and most widely studied signaling pathway downstream of these receptors involves activation and nuclear translocation of Smad proteins, which in turn regulate gene transcription through multiple interactions with distinct sets of transcription factors in a cell type-specific manner (1, 2). Although less well understood, Smad-independent pathways have also been described in a variety of cell systems and involve the activation of MAP kinases, small GTPases, and Ca 2ϩ mobilization (3).Identification of cell-intrinsic factors controlling the specification and function of pancreatic endocrine cells is of major importance for understanding the regulation of blood-glucose homeostasis. The characterization of signals regul...

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

“…2b), indicating that, by 2 months of age, the mutants had begun to develop glucose intolerance. These results parallel the responses previously observed in mice lacking the ALK7 receptor, one of the two type I receptors for activin B, which show hyperinsulinaemia from early stages but develop insulin resistance and glucose intolerance over time [17].…”

“…Insulin measurements and glucose tolerance test A glucose tolerance test was performed as described [17] after overnight fasting. Serum insulin was measured with an ultrasensitive mouse insulin ELISA kit (Mercodia, Stockholm, Sweden) from tail blood at the indicated time points before and after i.p.…”

“…We have previously shown that the type I receptor ALK7 is a negative regulator of pancreatic beta cell function [17]. ALK7 is expressed by all major islet cell types and, together with the type II receptor ACTRIIB, can signal in response to several members of the TGF-β superfamily, including activin B, but not activin A [18][19][20][21][22].…”

“…On the other hand, both activin proteins are able to signal through the related receptor ALK4. Mutant mice lacking ALK7 exhibit fasting hyperinsulinaemia, and pancreatic islets derived from Alk7 (also known as Acvr1c) mutants show enhanced GSIS [17]. Similar to Alk7 knockouts, mutant mice lacking activin B display high serum insulin levels as adults [17], suggesting that activin B might function as an endogenous suppressor of insulin secretion in pancreatic islets.…”

RNAi screen for kinases and phosphatases that play a role in antigen presentation by dendritic cells

“…It is therefore likely that Prkab1, Nek8 (Supporting Information Fig. 3), Ptpr6, Ppp3r, Dlgh3, and Sbk2 are novel and specific regulators of crosspresentation, without significantly affecting MHC class II presentation.We focused on one of the hits, Acvr1c, also known as Alk7, a type I receptor for the TGF-β family of signaling molecules, implicated in the regulation of adipose tissue accumulation [10] and pancreatic β-cell function [11], but no reports on a role in immunity.By measuring protein levels in response to knockdown with different shRNAs, we found a good correlation between Acvr1c protein levels and T-cell proliferation resulting from BMDC antigen cross-presentation (Fig. 1C).…”