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Raft-mediated Src homology 2 domain-containing proteintyrosine phosphatase 2 (SHP-2) regulation in microglia.

Authors
Kim, HY; Park, SJ; Joe, EH; Jou, I
Citation
The Journal of biological chemistry, 281(17):11872-11878, 2006
Journal Title
The Journal of biological chemistry
ISSN
0021-92581083-351X
Abstract
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signals play important roles in cell proliferation, apoptosis, and inflammation, and they recently have been considered as therapeutic targets for suppressing oncogenesis and inflammatory process. Phosphatases including Src homology 2 domain-containing protein-tyrosine phosphatases (SHPs), are well known as negative regulators of the JAK-STAT pathway, but their precise mechanisms are largely unknown. Based on our previous finding that in cultured rat brain microglia, gangliosides induce rapid and transient activation of the JAK-STAT pathway, we hypothesized that raft-mediated SHP-2 activation is involved in transient activation of JAK-STAT signaling by gangliosides. We first used Western blot analysis to confirm that gangliosides rapidly induce the phosphorylation of SHP-2. This was inhibited by pretreatment with the lipid raft disrupter filipin and was restored following filipin removal. Immunostaining using antibodies directed against p-SHP-2 and flotillin-1 revealed ganglioside-induced clustering and polarization of p-SHP-2 in membrane rafts. Raft-associated regulation of SHP-2 was further demonstrated in fractionation experiments using detergent and detergent-free sucrose gradient ultracentrifugation. Rapid SHP-2 recruitment to detergent-insoluble raft fractions by gangliosides was inhibited by filipin, further indicating the involvement of rafts. We also confirmed by immunoprecipitation that SHP-2 rapidly binds in a raft-dependent manner to JAK2 in response to gangliosides. Our study therefore showed that transient activation of the JAK-STAT pathway by gangliosides is accomplished by SHP-2 in a raft-dependent manner in brain microglia.
MeSH terms
AnimalsCell Membrane/metabolismFilipin/pharmacologyGangliosides/metabolismGene Expression Regulation*ImmunoprecipitationIntracellular Signaling Peptides and Proteins/metabolism*Janus Kinase 2Membrane Microdomains/metabolism*Membrane Proteins/metabolismMiceMicroglia/enzymology*PhosphorylationProtein Phosphatase 2Protein Tyrosine Phosphatase, Non-Receptor Type 11Protein Tyrosine Phosphatases/metabolism*Protein-Tyrosine Kinases/metabolismProto-Oncogene Proteins/metabolismRatsRats, Sprague-DawleySH2 Domain-Containing Protein Tyrosine PhosphatasesSTAT3 Transcription Factor/metabolismSignal Transduction*src Homology Domains
DOI
10.1074/jbc.M511706200
PMID
16507579
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
AJOU Authors
김, 희영조, 은혜주, 일로
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