MEK partner 1 (MP1): regulation of oligomerization in MAP kinase signaling.
Specificity in signal transduction can be achieved through scaffolds, anchors, and adapters that assemble generic signal transduction components in specific combinations and locations. MEK Partner-1 (MP1) was identified as a potential "scaffold" protein for the mammalian extracellular signal-regulated kinase (ERK) pathway. To gain insight into the interactions of MP1 with the ERK pathway, we analyzed the ability of MP1 to bind to MEK1, ERK1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major MP1 peaks: a broad high molecular weight peak and a 28 kDa complex. An MP1 mutant that lost MEK1 binding no longer enhanced RasV12-stimulated ERK1 activity, and functioned as a dominant negative, consistent with the concept that MP1 function depends on facilitating these oligomerizations. Activation of the ERK pathway by serum or by RasV12 did not detectably affect MP1-MP1 dimerization or MP1-MEK1 interactions, but caused the dissociation of the MP1-ERK1 complex. Surprisingly, pharmacological inhibition of ERK activation did not restore the complex, suggesting that regulation of complex formation occurs independently of ERK phosphorylation. These results support the concept that MP1 functions as a regulator of MAP kinase signaling by binding to MEK1 and regulating its association with a larger signaling complex that may sequentially service multiple molecules of ERK.
Sharma
Charu
C
Department of Microbiology and Cancer Center, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Vomastek
Tomás
T
Tarcsafalvi
Adel
A
Catling
Andrew D
AD
Schaeffer
Hans-Joerg
HJ
Eblen
Scott T
ST
Weber
Michael J
MJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation; D017353:Gene Deletion; D006801:Humans; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D044967:Serum; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins