Investigation of the molecular mechanisms underlying growth factor synergy: the role of ERK 2 activation in synergy.

2.50
Hdl Handle:
http://hdl.handle.net/10541/92759
Title:
Investigation of the molecular mechanisms underlying growth factor synergy: the role of ERK 2 activation in synergy.
Authors:
Pearson, M A; O'Farrell, A M; Dexter, T Michael; Whetton, Anthony D; Owen-Lynch, P J; Heyworth, Clare M
Abstract:
Stem Cell Factor (SCF), the ligand for the c-kit proto-oncogene, has been shown to synergistically interact with other cytokines, enhancing the responsiveness of haemopoietic precursors. In this study we have examined the effects of SCF, in combination with interleukin-3 (IL-3), on FDCP-Mix A4 cells, a murine, multipotent, haemopoietic progenitor cell line. Low concentration of IL-3 act to enhance cell survival but do not stimulate proliferation in A4 cells. Similarly, SCF when added alone, acts as a good survival stimulus, but is a poor proliferative stimulus. However, in combination with low concentrations of IL-3, SCF stimulates a synergistic enhancement of proliferation leading to a large increase in cell number after seven days. The synergy observed was not due to SCF stimulated alterations in the mRNA, protein levels or affinity of the IL-3 receptors. Therefore, interactions between cytokines at the level of cytoplasmic signalling pathways were investigated. IL-3 stimulated the rapid and transient tyrosine phosphorylation of several proteins (including those of molecular weights 130, 110, 100, 95, 80, 65, 50 and 45 kDa). Some of these proteins were identified as the Src Homology Collagen (SHC) protein, Janus kinase (JAK-2) and the Mitogen Activated Protein Kinase isoforms ERK 1 and ERK 2. IL-3 also stimulated a transient increase in the activity of both ERK 1 and 2. SCF stimulated a rapid and transient increase in the tyrosine phosphorylation of ERK 1 and ERK 2 although, coaddition of SCF with IL-3, caused no gross differences in the phosphorylation of SHC, JAK-2 or ERKs compared to those observed with IL-3 alone. Coaddition of SCF and low concentration of IL-3 stimulated a reproducible synergistic increase in the activity of ERK 2, whereas only an additive increase in the activity of ERK 1 was observed. These results suggest that ERK 2 activation represents a point at which the two pathways, stimulated by IL-3 and SCF, interact synergistically.
Affiliation:
Cancer Research Campaign Laboratories, Paterson Institute for Cancer Research, Manchester, UK.
Citation:
Investigation of the molecular mechanisms underlying growth factor synergy: the role of ERK 2 activation in synergy. 1998, 15 (4):293-306 Growth Factors
Journal:
Growth Factors
Issue Date:
1998
URI:
http://hdl.handle.net/10541/92759
PubMed ID:
9714913
Type:
Article
Language:
en
ISSN:
0897-7194
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPearson, M Aen
dc.contributor.authorO'Farrell, A Men
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorWhetton, Anthony Den
dc.contributor.authorOwen-Lynch, P Jen
dc.contributor.authorHeyworth, Clare Men
dc.date.accessioned2010-02-23T13:22:02Z-
dc.date.available2010-02-23T13:22:02Z-
dc.date.issued1998-
dc.identifier.citationInvestigation of the molecular mechanisms underlying growth factor synergy: the role of ERK 2 activation in synergy. 1998, 15 (4):293-306 Growth Factorsen
dc.identifier.issn0897-7194-
dc.identifier.pmid9714913-
dc.identifier.urihttp://hdl.handle.net/10541/92759-
dc.description.abstractStem Cell Factor (SCF), the ligand for the c-kit proto-oncogene, has been shown to synergistically interact with other cytokines, enhancing the responsiveness of haemopoietic precursors. In this study we have examined the effects of SCF, in combination with interleukin-3 (IL-3), on FDCP-Mix A4 cells, a murine, multipotent, haemopoietic progenitor cell line. Low concentration of IL-3 act to enhance cell survival but do not stimulate proliferation in A4 cells. Similarly, SCF when added alone, acts as a good survival stimulus, but is a poor proliferative stimulus. However, in combination with low concentrations of IL-3, SCF stimulates a synergistic enhancement of proliferation leading to a large increase in cell number after seven days. The synergy observed was not due to SCF stimulated alterations in the mRNA, protein levels or affinity of the IL-3 receptors. Therefore, interactions between cytokines at the level of cytoplasmic signalling pathways were investigated. IL-3 stimulated the rapid and transient tyrosine phosphorylation of several proteins (including those of molecular weights 130, 110, 100, 95, 80, 65, 50 and 45 kDa). Some of these proteins were identified as the Src Homology Collagen (SHC) protein, Janus kinase (JAK-2) and the Mitogen Activated Protein Kinase isoforms ERK 1 and ERK 2. IL-3 also stimulated a transient increase in the activity of both ERK 1 and 2. SCF stimulated a rapid and transient increase in the tyrosine phosphorylation of ERK 1 and ERK 2 although, coaddition of SCF with IL-3, caused no gross differences in the phosphorylation of SHC, JAK-2 or ERKs compared to those observed with IL-3 alone. Coaddition of SCF and low concentration of IL-3 stimulated a reproducible synergistic increase in the activity of ERK 2, whereas only an additive increase in the activity of ERK 1 was observed. These results suggest that ERK 2 activation represents a point at which the two pathways, stimulated by IL-3 and SCF, interact synergistically.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.meshAdaptor Proteins, Signal Transducing-
dc.subject.meshAdaptor Proteins, Vesicular Transport-
dc.subject.meshAnimals-
dc.subject.meshCalcium-Calmodulin-Dependent Protein Kinases-
dc.subject.meshCell Division-
dc.subject.meshCell Line-
dc.subject.meshCell Survival-
dc.subject.meshDrug Synergism-
dc.subject.meshEnzyme Activation-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshInterleukin-3-
dc.subject.meshJanus Kinase 2-
dc.subject.meshMice-
dc.subject.meshMitogen-Activated Protein Kinase 1-
dc.subject.meshMitogen-Activated Protein Kinase 3-
dc.subject.meshMitogen-Activated Protein Kinases-
dc.subject.meshPhosphotyrosine-
dc.subject.meshProtein-Tyrosine Kinases-
dc.subject.meshProteins-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshShc Signaling Adaptor Proteins-
dc.subject.meshSignal Transduction-
dc.subject.meshStem Cell Factor-
dc.titleInvestigation of the molecular mechanisms underlying growth factor synergy: the role of ERK 2 activation in synergy.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Laboratories, Paterson Institute for Cancer Research, Manchester, UK.en
dc.identifier.journalGrowth Factorsen

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