SOCS3 mediates feedback inhibition of the leptin receptor via Tyr(985)

During leptin signaling, each of the phosphorylated tyrosine residues on th e long form of the leptin receptor (LRb) mediates distinct signals. Phospho rylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and t ranscriptional activation, while phosphorylated Tyr(985) binds the tyrosine phosphatase SHP-2 and reportedly mediates both activation of ERK kinases a nd inhibition of LRb-mediated STAT3 activation. We show here that although mutation of Tyr985 does not alter STAT3 signaling by erythropoietin recepto r-LRb (ELR) chimeras in transfected 293 cells at short times of stimulation , this mutation enhances STAT3 signaling at longer times of stimulation (>6 h). These data suggest that Tyr(985) may mediate feedback inhibition of LR b signaling by an LRb-induced LRb inhibitor, such as SOCS3. Indeed, SOCS3 b inds specifically to phosphorylated Tyr(985) Of LRb, and SOCS3 fails to inh ibit transcription by ELR following mutation of Tyr985, suggesting that SOC S3 inhibits LRb signaling by binding to phosphorylated Tyr(985). Additional ly, overexpression of SOCS3, but not SHP-2, impairs ELR signaling, and the overexpression of SHP-2 blunts SOCS3-mediated inhibition of ELR signaling. Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr985 Of LRb mediates feedback inhibi tion of LRb signaling by binding to LRb-induced SOCS3.