CDB15:0001118 NODAL — ACVR1C
Experimentally validated in Human, Mouse; Orthology-inferred in Human, Rat, Frog, Zebrafish, Chicken, Macaque, Pig, Dog, Cow, Chimp, Horse, Marmoset, Sheep, Mouse
Title
Journal:; Year Published:
Abstract
The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development.
Genes & development, 2001; PubMed, Mus Musculus Nodal — Mus Musculus Acvr1c
ABSTRACT: Nodal proteins have crucial roles in mesendoderm formation and left-right patterning during vertebrate development. The molecular mechanisms of signal transduction by Nodal and related ligands, however, are not fully understood. In this paper, we present biochemical and functional evidence that the orphan type I serine/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1). Receptor reconstitution experiments indicate that ALK7 collaborates with ActRIIB to confer responsiveness to Xnr1 and Nodal. Both receptors can independently bind Xnr1. In addition, Cripto, an extracellular protein genetically implicated in Nodal signaling, can independently interact with both Xnr1 and ALK7, and its expression greatly enhances the ability of ALK7 and ActRIIB to respond to Nodal ligands. The Activin receptor ALK4 is also able to mediate Nodal signaling but only in the presence of Cripto, with which it can also interact directly. A constitutively activated form of ALK7 mimics the mesendoderm-inducing activity of Xnr1 in Xenopus embryos, whereas a dominant-negative ALK7 specifically blocks the activities of Nodal and Xnr1 but has little effect on other related ligands. In contrast, a dominant-negative ALK4 blocks all mesoderm-inducing ligands tested, including Nodal, Xnr1, Xnr2, Xnr4, and Activin. In agreement with a role in Nodal signaling, ALK7 mRNA is localized to the ectodermal and organizer regions of Xenopus gastrula embryos and is expressed during early stages of mouse embryonic development. Therefore, our results indicate that both ALK4 and ALK7 can mediate signal transduction by Nodal proteins, although ALK7 appears to be a receptor more specifically dedicated to Nodal signaling.
Identification of novel isoforms of activin receptor-like kinase 7 (ALK7) generated by alternative splicing and expression of ALK7 and its ligand, Nodal, in human placenta.
Biology of reproduction, 2003; PubMed, Homo sapiens NODAL — Homo sapiens ACVR1C
ABSTRACT: Members of the transforming growth factor (TGF) beta family play critical roles in regulating placental functions. Using polymerase chain reaction (PCR)-based strategies, we have cloned four transcripts encoding full-length activin receptor-like kinase 7 (ALK7) and three novel ALK7 isoforms from the human placenta. The full-length ALK7 has 493 amino acids and exhibits all characteristics of TGFbeta type I receptors, including an activin receptor-binding domain, a transmembrane domain, a GS domain, and a serine/threonine kinase domain. The three ALK7 isoforms identified include a truncated ALK7 (tALK7) and two soluble proteins designated as soluble ALK7a (sALK7a) and soluble ALK7b (sALK7b). The tALK7 lacks the first 50 amino acids of the full-length ALK7, resulting in a truncated receptor-binding domain. Both sALK7a and sALK7b lack transmembrane and GS domains. The ALK7 gene, located on chromosome 2q24.1, is composed of at least nine exons and eight introns. The isoforms of ALK7 are generated by alternative splicing. Transcripts encoding the sALK7 isoforms differ from the full-length transcript by lacking exon III or both exons III and IV in sALK7a and sALK7b, respectively. The transcript for tALK7 uses an alternative exon located within the first intron of the full-length transcript. These results indicate that four distinct proteins are encoded by the human ALK7 gene. Both reverse transcription-PCR and Western blot analysis showed that ALK7 and its isoforms are expressed in human placentae of different stages of pregnancy and that their expression is developmentally regulated. In addition, mRNA expression of Nodal, a ligand for ALK7, was also detected in placentae of different gestational age. The role of Nodal and ALK7 in human placenta is currently under investigation.