ALK5TGFBR1

ALK5TGFBR1, also known as activin receptor-like kinase 5 or transforming growth factor beta receptor 1 (TGFBR1), is a receptor serine/threonine kinase that is part of the TGF-β signaling pathway. It functions as the type I receptor in a receptor complex that mediates cellular responses to TGF-β ligands. The protein is a single-pass transmembrane receptor with an extracellular domain for ligand binding, a transmembrane segment, and an intracellular kinase domain containing the GS box that regulates activation.

In canonical signaling, TGF-β ligands first bind to the type II receptor, which recruits and phosphorylates ALK5/TGFBR1. Activated ALK5 then phosphorylates SMAD2 and SMAD3, which partner with SMAD4 and translocate to the nucleus to regulate transcription of genes involved in cell cycle control, extracellular matrix production, differentiation, and apoptosis. ALK5 can also activate non-SMAD pathways such as MAPK and PI3K-Akt, contributing to diverse cellular outcomes.

Clinical significance includes a role in developmental and connective tissue disorders and broader disease processes. Mutations in TGFBR1 cause Loeys-Dietz syndrome type 1, a dominantly inherited connective tissue disorder characterized by arterial aneurysms and craniofacial abnormalities. In cancer and fibrotic disease research, alterations in TGFBR1 signaling are studied for their influence on tumor suppression, tumor progression, and tissue fibrosis. Common TGFBR1 variants, such as the TGFBR1*6A allele, have been investigated for potential associations with cancer risk, though findings are mixed.

Therapeutically, agents that modulate ALK5 activity are under investigation for fibrotic diseases and cancer, reflecting the receptor’s central role in TGF-β signaling.