THE MITOGEN-ACTIVATED PROTEIN-KINASE PHOSPHATASES PAC1, MKP-1, AND MKP-2 HAVE UNIQUE SUBSTRATE SPECIFICITIES AND REDUCED ACTIVITY IN-VIVO TOWARD THE ERK2 SEVENMAKER MUTATION

Mitogen-activated protein (MAP) kinases can be grouped into three stru ctural families, ERK, JNK, and p38, which are thought to carry out uni que functions within cells. We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the d ual specific phosphatases PAC1 and MKP-1 previously have been implicat ed in the in vivo inactivation of ERK or of ERK and JNK respectively. Here we characterize a new MAP kinase phosphatase, MKP-2, that is indu ced in human peripheral blood T cells with phorbol 12-myristate 13-ace tate and is expressed in a variety of nonhematopoietic tissues as well . We show that the in vivo substrate specificities of individual phosp hatases are unique, PAC1, MKP-2, and MKP-1 recognize ERK and p38, ERK and JNK, and ERK, p38, and JNK, respectively. Thus, individual MAP kin ase phosphatases can differentially regulate the potential for cross-t alk between the various MAP kinase pathways. A hyperactive allele of E RK2 (D319N), analogous to the Drosophila sevenmaker gain-of-function m utation, has significantly reduced sensitivity to all three MAP kinase phosphatases in vivo.