A Novel Type I Receptor Serine-Threonine Kinase Predominantly Expressed in the Adult Central Nervous System

Abstract

Receptor serine-threonine kinases (RSTK) mediate inhibitory as well as stimulatory signals for growth and differentiation by binding to members of the transforming growth factor-␤ (TGF-␤) superfamily. Over 12 different RSTKs have been isolated so far, displaying wide expression in peripheral tissues and in the nervous system. Here we report the isolation and characterization of a novel type I RSTK termed activin receptor-like kinase-7 (ALK-7) that, unlike other members of this receptor family, is predominantly expressed in the adult central nervous system. The ALK-7 gene encodes a 55-kDa cell-surface protein that exhibits up to 78% amino acid sequence identity in the kinase domain to previously isolated type I receptors for TGF-␤ and activin. In the extracellular domain, however, ALK-7 is more divergent, displaying comparable similarities with all members of the ALK subfamily. RNase protection and in situ hybridization studies demonstrated a highly specific mRNA distribution restricted to neurons in several regions of the adult rat central nervous system, including cerebellum, hippocampus, and nuclei of the brainstem. Receptor reconstitution and cross-linking experiments indicated that ALK-7 can form complexes with type II RSTKs for TGF-␤ and activin in a ligand-dependent manner, although direct binding of ALK-7 to ligand in these complexes could not be demonstrated. The specific expression pattern of ALK-7, restricted to the postnatal central nervous system, indicates that this receptor may play an important role in the maturation and maintenance of several neuronal subpopulations. TGF-␤1 superfamily members are pleiotropic growth factors with a wide range of activities in many different tissues. They can be subdivided, based on their structural and biological similarities, into three subfamilies, the TGF-␤s (TGF-␤1 to ␤3), the activins, and the heterogeneous decapentaplegic-and Vg1-related group. The latter includes the mammalian bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). Other more distantly related members include glial cell line-derived neurotrophic factor (GDNF) and Mü llerian inhibiting substance (for review see Ref.

Expression of transforming growth factor‐β superfamily receptors in rat eyes

“…They consist of two families; the type I receptor family and the type II receptor family Wrana et al 1994;Yamashita et al 1994Yamashita et al , 1996Heldin et al 1997). Seven type I receptors have been cloned (Franzén et al 1993;ten Dijke et al 1994aten Dijke et al , 1994bCárcamo et al 1994;Yamashita et al 1996;Rydén et al 1996). Type I receptors have a highly conserved sequence, the GS domain, which type II receptors lack ).…”

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

“…Unlike ALK4, however, ALK7 does not mediate activin A signaling (15,16). ALK7 is dispensable for mouse embryogenesis (17), which suggests alternative functions for this receptor in postnatal development and tissue homeostasis.…”

“…ALK7 is dispensable for mouse embryogenesis (17), which suggests alternative functions for this receptor in postnatal development and tissue homeostasis. ALK7 is expressed in several organs involved in metabolic regulation, including pancreas, adipose tissue, gut, and brain (16,(18)(19)(20), but the physiological function of this receptor has been unknown. In this study, we have investigated the roles of ALK7 in metabolic control and the organization and function of the endocrine pancreas.…”

ALK7 Gene Polymorphism is Associated with Metabolic Syndrome Risk and Cardiovascular Remodeling

“…To date, a total of seven type I receptors (ALK1-7) have been cloned from mammals 7 . ALK7, which was initially cloned from the rat brain 8,9 , has been mapped to the gene locus 2q24.1-q3 in humans. Up to now, four ALK7 transcripts generated from alternative splicing of the ALK7 gene have been described 10,11 .…”

“…ALK7 is expressed in several organs involved in metabolic regulation, including the pancreas and adipose tissue 8,9,12 . Reportedly, ALK7 induces apoptosis of pancreatic β-cells and β-cell lines via the activation of downstream pathways 13 , and negatively regulates glucose-stimulated insulin release by β-cells 14 .…”