PROSITE documentation PDOC00212

Receptor tyrosine kinase class II signature

A number of growth factors stimulate mitogenesis by interacting with a family of cell surface receptors which possess an intrinsic, ligand-sensitive, protein tyrosine kinase activity [1]. These receptor tyrosine kinases (RTK) all share the same topology: an extracellular ligand-binding domain, a single transmembrane region and a cytoplasmic kinase domain. However they can be classified into at least five groups. The prototype for class II RTK's is the insulin receptor, a heterotetramer of two α and two β chains linked by disulfide bonds. The α and β chains are cleavage products of a precursor molecule. The α chain contains the ligand binding site, the β chain transverses the membrane and contains the tyrosine protein kinase domain. The receptors currently known to belong to class II are:

• Insulin receptor from vertebrates.
• Insulin growth factor I receptor from mammals.
• Insulin receptor-related receptor (IRR), which is most probably a receptor for a peptide belonging to the insulin family.
• Insects insulin-like receptors.
• Molluscan insulin-related peptide(s) receptor (MIP-R).
• Insulin-like peptide receptor from Branchiostoma lanceolatum.
• The Drosophila developmental protein sevenless, a putative receptor for positional information required for the formation of the R7 photoreceptor cells.
• The trk family of receptors (NTRK1, NTRK2 and NTRK3), which are high affinity receptors for nerve growth factor and related neurotrophic factors (BDNF and NT-3).

And the following uncharacterized receptors:

• ROS.
• LTK (TYK1).
• EDDR1 (cak, TRKE, RTK6).
• NTRK3 (Tyro10, TKT).
• A sponge putative receptor tyrosine kinase.

While only the insulin and the insulin growth factor I receptors are known to exist in the tetrameric conformation specific to class II RTK's, all the above proteins share extensive homologies in their kinase domain, especially around the putative site of autophosphorylation. Hence, we developed a signature pattern for this class of RTK's, which includes the tyrosine residue, itself probably autophosphorylated.