The Lipoxin A4 receptor is coupled to SHP-2 activation: implications for regulation of receptor tyrosine kinases.
Mesangial cell proliferation is pivotal to the pathology of glomerular injury in inflammation. We have previously reported that lipoxins, endogenously produced eicosanoids with anti-inflammatory and pro-resolution bioactions, can inhibit mesangial cell proliferation in response to several agents. This process is associated with elaborate receptor cross-talk involving modification receptor tyrosine kinase phosphorylation (McMahon, B., Mitchell, D., Shattock, R., Martin, F., Brady, H. R., and Godson, C. (2002) FASEB J. 16, 1817-1819). Here we demonstrate that the lipoxin A(4) (LXA(4)) receptor is coupled to activation and recruitment of the SHP-2 (SH2 domain-containing tyrosine phosphatase-2) within a lipid raft microdomain. Using site-directed mutagenesis of the cytosolic domain of the platelet-derived growth factor receptor beta (PDGFRbeta), we report that mutation of the sites for phosphatidylinositol 3-kinase (Tyr(740) and Tyr(751)) and SHP-2 (Tyr(763) and Tyr(1009)) recruitment specifically inhibit the effect of LXA(4) on the PDGFRbeta signaling; furthermore inhibition of SHP-2 expression with short interfering RNA constructs blocked the effect of LXA(4) on PDGFRbeta phosphorylation. We demonstrate that association of the PDGFRbeta with lipid raft microdomains renders it susceptible to LXA(4)-mediated dephosphorylation by possible reactivation of oxidatively inactivated SHP-2. These data further elaborate on the potential mechanisms underlying the anti-inflammatory, proresolution, and anti-fibrotic bioactions of lipoxins.
Mitchell
Derick
D
School of Medicine and Medical Science, Diabetes Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
O'Meara
Sarah J
SJ
Gaffney
Andrew
A
Crean
John K G
JK
Kinsella
B Therese
BT
Godson
Catherine
C
D002460:Cell Line; D049109:Cell Proliferation; D005920:Glomerular Mesangium / Q000201:enzymology* / Q000293:injuries; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000201:enzymology* / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000235:genetics
C105101:FPR2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D019869:Phosphatidylinositol 3-Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D054648:Protein Phosphatase 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases