Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2.
The src homology 2 (SH2) domain-containing protein-tyrosine phosphatase SHP-2 has been implicated as an important positive regulator of several mitogenic signaling pathways. SHP-2 has more recently been shown to be tyrosine phosphorylated and recruited to the gp130 component of the ciliary neurotrophic factor (CNTF) receptor complex upon stimulation with CNTF. CNTF does not, however, have a proliferative effect on responsive cells, but rather enhances the survival and differentiation of sympathetic, motor, and sensory neurons. In this study, expression of an interfering mutant of SHP-2 in the neuroblastoma cell line NBFL increased CNTF induction of a vasoactive intestinal peptide (VIP) reporter gene, and in cultures of sympathetic neurons, it resulted in an up-regulation of endogenous VIP and substance P (SP) gene expression. Members of the CNTF family of cytokines transmit their signal by activating signaling pathways involving both STAT and Fos-Jun transcription factors. In CNTF-stimulated NBFL cells that constitutively express the SHP-2 interfering mutant, there was increased and prolonged formation of STAT/DNA complexes, but decreased AP-1 binding activity, that mirrored a down-regulation of c-fos expression both at the mRNA and protein level. Taken together, these data indicate that SHP-2 has dual and opposing roles in a signaling cascade triggered by the same ligand, as illustrated by its ability to differentially regulate the levels of activity of both STAT and AP-1 transcription factors.
Servidei
T
T
Neurosurgical Service, Molecular Neuro-Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.
Aoki
Y
Y
Lewis
S E
SE
Symes
A
A
Fink
J S
JS
Reeves
S A
SA
D000818:Animals; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005728:Ganglia, Sympathetic / Q000166:cytology; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013373:Substance P / Q000096:biosynthesis; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000096:biosynthesis
D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases