Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein] Interacts with MORG1 (By similarity). Interacts with SGK1 (PubMed:19447520). Interacts with KSR1 (PubMed:10409742). Interacts with KSR1 and BRAF; the interaction with KSR1 mediates KSR1-BRAF dimerization (PubMed:29433126). Interacts with GLS (PubMed:22538822). Membrane localization is probably regulated by its interaction with KSR1. MAPKK is itself dependent on Ser/Thr phosphorylation for activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1). Phosphorylated by MAP2K1/MEK1 (By similarity). (Microbial infection) Acetylation of Ser-222 and Ser-226 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway. The disease is caused by variants affecting the gene represented in this entry. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.