PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif

Protein kinases and phosphatases regulate the activity of extracellular sig nal-regulated kinases 1 and 2 (ERK1/2) by controlling the phosphorylation o f specific residues. We report the physical and functional association of E RK1/2 with the PTP-SL and STEP protein tyrosine phosphatases (PTPs), Upon b inding, the N-terminal domains of PTP-SL and STEP were phosphorylated by ER K1/2, whereas these PTPs dephosphorylated the regulatory phosphotyrosine re sidues of ERK1/2 and inactivated them. A sequence of 16 amino acids in PTP- SL was identified as being critical for ERK1/2 binding and termed kinase in teraction motif (KIM) (residues 224-239); it was shown to be required for p hosphorylation of PTP-SL by ERK1/2 at Thr(253). Go-expression of ERK2 with catalytically active PTP-SL in COS-7 cells impaired the EGF-induced activat ion of ERK2, whereas a PTP-SL mutant, lacking PTP activity, increased the E RK2 response to EGF. This effect was dependent on the presence of the KIM o n PTP-SL, Furthermore, ERK1/2 activity was downregulated in 3T3 cells stabl y expressing PTP-SL, Our findings demonstrate the existence of a conserved ERK1/2 interaction motif within the cytosolic noncatalytic domains of PTP-S L and STEP, which is required for the regulation of ERK1/2 activity and for phosphorylation of the PTPs by these kinases, Our findings suggest that PT P-SL and STEP act as physiological regulators of the ERK1/2 signaling pathw ay.