transautophosphorylation

Transautophosphorylation is a form of autophosphorylation in which two kinase molecules within a dimer phosphorylate each other on specific residues, usually tyrosine. This inter-molecular phosphorylation contrasts with cis-autophosphorylation, where a single molecule phosphorylates residues within its own activation loop or other sites.

In many receptor tyrosine kinases, ligand binding promotes dimerization, bringing the kinase domains into close contact. Each kinase domain then phosphorylates tyrosine residues on the partner monomer’s activation loop and other regulatory sites. This trans phosphorylation stabilizes the active conformation, enhances catalytic activity, and creates phosphotyrosine docking sites for SH2- or PTB-domain signaling proteins, thereby shaping downstream pathways such as MAPK and PI3K-Akt.

Transautophosphorylation is a key regulatory step for signaling initiated by receptor tyrosine kinases, including members of the EGFR/ERBB family, as well as other RTKs like VEGFR and FGFR. The insulin receptor is a well-studied example in which activation loop phosphorylation occurs in a trans manner across the receptor dimer. Disruptions or constitutive activation of transautophosphorylation can contribute to diseases such as cancer and metabolic disorders, whereas proper regulation is essential for controlled cellular responses to growth factors.