Activin isoforms signal through type I receptor serine/threonine kinase ALK7

doi:10.1016/j.mce.2004.03.009

Molecular and Cellular Endocrinology

Volume 220, Issues 1–2, 31 May 2004, Pages 59-65

https://doi.org/10.1016/j.mce.2004.03.009 Get rights and content

Abstract

Activins play a fundamental role in cell differentiation and development. Activin A signaling is mediated through a combination of activin type II receptors (ActRIIs) and the activin type IB receptor, ALK4. Signaling receptors of other activin isoforms remain to be elucidated. Here, we found that activin AB and activin B are ligands for ALK7. ALK7 is an orphan receptor serine/threonine kinase expressed in neuroendocrine tissues including pancreatic islets. The combination of ActRIIA and ALK7, preferred by activin AB and activin B but not by activin A, is responsible for activin-mediated secretion of insulin from pancreatic β cell line, MIN6. In contrast, all activins activate a combination of ActRIIA and ALK4 with various levels of potency. Thus, variation in activin signaling through type I receptors is dependent upon homo- and heterodimeric assembly of activin isoforms. Thus, the differential combination of receptor heterodimers mediates variation in activin isoform signaling.

Introduction

Activins mediate a wide range of biological actions on cell growth and differentiation (Gaddy-Kurten et al., 1995, Sugino and Tsuchida, 2000). Activins are homo- or heterodimers composed of two β subunits. To date, activins A, AB and B have been isolated from natural sources (Gaddy-Kurten et al., 1995, Sugino and Tsuchida, 2000). The βC and βE subunits are expressed predominantly in the liver, but their function is yet to be determined (Lau et al., 2000).

Activins signal through two types of transmembrane serine/threonine kinase receptors, types I and II (Gaddy-Kurten et al., 1995, Sugino and Tsuchida, 2000). Type II receptors can bind activins independently (Mathews and Vale, 1991). Type I receptors are recruited to the type II receptor and produce an activated receptor complex. Activated type I receptors interact with Smads, which regulates the transcription of selected genes (Tsuchida, 2004). Of the three activin isoforms isolated, activin A and activin AB have equivalent biological activity levels. Their activities are significantly higher than that of activin B (Nakamura et al., 1992). Low biological activity of activin B is suggestive of the existence of different receptors for activin B (Corrigan et al., 1991, Mathews and Vale, 1991, Nakamura et al., 1992). The inhibin βA and βB subunits, exhibit significantly different patterns of mRNA expression and immunolabeling. Whereas the mRNA for inhibin βA is distributed in the limb bud, whisker, skin and distinct regions of the nervous system, the mRNA for inhibin βB is highly expressed in the developing brain, salivary gland, mammary gland, and the epithelium of the stomach and esophagus (Feijen et al., 1994, Roberts et al., 1991).

Gene inactivation studies have shown that the phenotype of the inhibin βA and inhibin βB knockout mouse are clearly different, indicating a lack of functional redundancy between activins A and B during embryogenesis (Matzuk et al., 1995, Vassalli et al., 1994). Furthermore introducing inhibin βB gene into inhibin βA knockout allele could compensate inhibin βA phenotype in a dosage sensitive manner, but evoke additional phenotypes (Brown et al., 2000). These findings strongly suggest that the signaling mechanism of activin B and/or activin AB differs from that of activin A. In this study, we found that combination of ActRIIA and ALK7 is activated by activins AB and B. The expression of ALK7 determines the sensitivity of activin isoforms, and augments the response to activins AB and B. ALK7 is expressed abundantly in neuronal tissues, and until recently it was thought to be an orphan receptor serine/threonine kinase (Ryden et al., 1996, Reissmann et al., 2001, Tsuchida et al., 1996). ALK7 which confers sensitivity to activins AB and B, is co-expressed with ActRIIA in the brain, spinal cord, pancreas and duodenum. In contrast to the restricted expression pattern of ALK7, the activin type IB receptor, ALK4, is ubiquitously expressed. The differential heteromeric association of type II and type I receptors mediates variation in activin isoform signaling.

Section snippets

DNA construction

For the construction of the dominant negative ALK7, rat ALK7 cDNA was amplified by the polymerase chain reaction (PCR) using a combination of the sense primer 5′-CCTAAGCTTGATGACCCCAGCGCGCCGCTCCGCACTGA-3′, and the antisense primer 5′-CCGCTCGAGCTAAGATCTGAGGGTTTTTCCAGCATTGACAAGG-3′. Amplified DNA was subcloned in EcoRI–XhoI digested pcDNA3 (GIBCO BRL), and then sequenced. Resultant D/N ALK7 has extracellular domain, transmembrane domain, and intracellular 32 amino acids, but lacks GS domain and

Responsiveness of activin isoforms

Polymerase chain reaction analysis was used to survey a range of cells for endogenous expression of activin receptors (ActRIIA and ALK4). The mRNA for both ActRIIA and ALK4 was detected in all cells that respond to activin A including HEK293 and HT22 cells (Fig. 1). In contrast, cells expressing ALK7 are very rare. The mouse pancreatic β cell line, MIN6, is the only cell line identified to date that endogenously expresses mRNA for ALK7 (Fig. 1) (Watanabe et al., 1999).

We determined the

Discussion

In the present study, we describe the receptor system of activin isoforms. Although three activin isoforms are thought to signal through the same combination of receptors (Matzuk, 2000), we have identified here that activin signaling through type I receptors is dependent upon the activin isoforms. Importantly, the combination of the receptors ActRII and ALK7 can be activated by both activins AB and B. ALK7 was originally identified as an orphan receptor highly expressed in the nervous system (

Acknowledgments

We thank Dr. C.-H. Heldin for providing the reporter plasmids and Dr. J. Miyazaki for the mouse pancreatic β cells. This research was supported by the Ministry of Education, Science, Sports, Culture and Technology of Japan and also supported by grants from The Yamanouchi Foundation for Research on Metabolic Disorders, The Fujisawa Foundation, and Kyowa Hakko Kogyo Co. Ltd. to K.T.

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Activin isoforms signal through type I receptor serine/threonine kinase ALK7

Abstract

Introduction

Section snippets

DNA construction

Responsiveness of activin isoforms

Discussion

Acknowledgments

Cell

Rec. Prog. Horm. Res.

Exp. Neurol.

Cell

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell. Neurosci.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions

Nat. Genet.

Hybridization histochemical localization of activin receptor subtypes in rat brain, pituitary, ovary, and testis

Endocrinology

Evidence for an autocrine role of activin B within rat anterior pituitary cultures

Endocrinology