Regulation of p70 S6 kinase by complex formation between the Rac guanine nucleotide exchange factor (Rac-GEF) Tiam1 and the scaffold spinophilin.
Tiam1 is a ubiquitous guanine nucleotide exchange factor (GEF) that activates the Rac GTPase. We have shown previously that the N terminus of Tiam1 contributes to the signaling specificity of its downstream target Rac via association with IB2, a scaffold that promotes Rac activation of a p38 kinase cascade. Here we show that the N terminus of Tiam1 can influence Rac signaling specificity in a different way by interaction with spinophilin, a scaffold that binds to p70 S6 kinase, another protein regulated by Rac. In particular, spinophilin binding promotes the plasma membrane localization of Tiam1 and enhances the ability of Tiam1 to activate p70 S6 kinase. In contrast, spinophilin binding suppresses the ability of Tiam to activate Pak1, a different Rac effector. Finally, a mutant spinophilin that cannot bind to Tiam1 suppresses serum-induced p70 S6 kinase activation in cells, suggesting that a Tiam1/spinophilin complex contributes to p70 S6 kinase regulation by extracellular signals. These findings add to a growing body of evidence supporting the concept that some Rac-GEFs not only activate Rac GTPases but also participate in the selection of Rac effector by binding to particular scaffolds that complex with components of specific Rac effector pathways.
Buchsbaum
Rachel J
RJ
Department of Biochemistry, Tufts University School of Medicine, Boston, Massachussetts 02111, USA.
Connolly
Beth A
BA
Feig
Larry A
LA
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D001769:Blood; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D007163:Immunosorbent Techniques; D007668:Kidney; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014162:Transfection; D020798:Two-Hybrid System Techniques; D054462:p21-Activated Kinases; D020666:ras-GRF1 / Q000494:pharmacology; D000099273:Neurabins
D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D054462:p21-Activated Kinases; D020666:ras-GRF1; D000099273:Neurabins; C087334:TIAM1 protein, human; C513260:Tiam1 protein, mouse; C513259:Tiam1 protein, rat; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; C515906:Pak1 protein, rat