Sterile-20 (Ste20) is a serine/threonine kinase in Saccharomyces cerevisiae that is involved in relaying signals from G protein-coupled receptors to cyto-solic MAP kinase cascades. Mammalian protein kinases that display sequence similarity to Ste20 are divided into two groups, the PAK subfamily and the GCK subfamily. The PAK subfamily members contain a C-terminal catalytic domain and an N-terminal regulatory domain with a p21Rac/Cdc42-binding site, and these kinases can activate both p38 MAPK and JNK. The GCK subfamily members contain a C-terminal regulatory domain and an N-terminal catalytic domain, and they have diverse roles in many pathways, including the activation of ERK, JNK, p38 MAPK, and caspase-3. The mammalian Ste20-like kinases (MST kinases), also known as Krs proteins, are members of the GCK subfamily. Ksr-1 (MST-2) and Ksr-2 (MST-1) are both direct substrates of caspase-3 that accelerate caspase-3 activation. MST-3 is ubiquitously expressed in mammalian tissue and can phosphorylate exogenous substrates as well as itself. MST-4 is highly expressed in placenta, thymus, and peripheral blood leukocytes, and it specifically activates ERK.