Mode of receptor binding and activation by plasminogen-related growth factors

Hepatocyte growth factor/scatter factor (HGF/SF) and macrophage stimulating protein (MSP) are plasminogen-related kringle proteins that lost serine protease domain enzymatic activity and became ligands for cell surface tyrosine kinase receptors. They are activated by cleavage to disulfide-linked alphabeta chains. Surprisingly, despite structural similarities, the high affinity receptor binding regions of the two proteins are different: alpha chain for HGF, and beta chain for MSP. We propose that after cleavage exposes a beta chain binding site (high affinity for MSP, low affinity for HGF), monomeric ligand induces receptor dimerization and activation via alpha and beta chain binding sites of different affinity.