title: Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor.
abstract: Interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate proliferation, differentiation and apoptosis of target cells. Receptors for these cytokines consist of a cytokine-specific alpha subunit and a common shared beta c subunit. Tyrosine phosphorylation of the beta c is thought to play a critical role in mediating signal transduction events. We have examined the effect of mutation of beta c tyrosines on the activation of multiple signal transduction pathways. Activation of protein kinase B (PKB) required JAK2 and was inhibited by dominant-negative phosphatidylinositol 3-kinase (P13K). Overexpression of JAK2 was sufficient to activate both protein kinase B (PKB) and extracellular regulated kinase-1 (ERK1). Tyrosine 577 and 612 were found to be critical for the activation of PKB and ERK1, but not activation of STAT transcription factors. Activation of both PKB and ERK have been implicated in the regulation of proliferation and apoptosis. We generated GM-CSFR stable cell lines expressing receptor mutants to evaluate their effect on these processes. Activation of both PKB and ERK was perturbed, while STAT activation remained unaffected. Tyrosines 577 and 612 were necessary for optimal proliferation, however, mutation of these tyrosine residues did not affect GM-CSF mediated rescue from apoptosis. These data demonstrate that while phosphorylation of beta c tyrosine residues 577 and 612 are important for optimal cell proliferation, rescue from apoptosis can be mediated by alternative signalling routes apparently independent of PKB or ERK activation.
authors.affiliation: Department of Pulmonary Diseases, University Hospital Utrecht, The Netherlands.
authors.forename: P F
authors.initials: PF
authors.lastname: Dijkers
authors.forename: T B
authors.initials: TB
authors.lastname: van Dijk
authors.forename: R P
authors.initials: RP
authors.lastname: de Groot
authors.forename: J A
authors.initials: JA
authors.lastname: Raaijmakers
authors.forename: J W
authors.initials: JW
authors.lastname: Lammers
authors.forename: L
authors.initials: L
authors.lastname: Koenderman
authors.forename: P J
authors.initials: PJ
authors.lastname: Coffer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line / Q000378:metabolism; D002470:Cell Survival; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015848:Interleukin-5 / Q000378:metabolism*; D053614:Janus Kinase 2; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D053649:Receptors, Interleukin-5; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015848:Interleukin-5; D053614:Janus Kinase 2; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5; D011994:Recombinant Proteins; D014157:Transcription Factors; D014443:Tyrosine; C507926:Jak2 protein, mouse