PMID- 10449753 OWN - NLM STAT- MEDLINE DCOM- 19990909 LR - 20190501 IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 96 IP - 17 DP - 1999 Aug 17 TI - Leptin receptor activation of SH2 domain containing protein tyrosine phosphatase 2 modulates Ob receptor signal transduction. PG - 9677-82 AB - Leptin exerts its weight-reducing effects by binding to its receptor and activating signal transduction in hypothalamic neurons and other cell types. To identify the components of the leptin signal transduction pathway, an approach was developed in which bacterially expressed phosphorylated fragments of Ob receptor b (Ob-Rb) were used as affinity agents. Leptin binding to the Ob-Rb form of the leptin receptor leads to tyrosyl phosphorylation of the cytoplasmic domain of its receptor. Two of the three cytoplasmic tyrosines of Ob-Rb, at positions 985 and 1138, are phosphorylated after leptin treatment. Affinity chromatography using a tyrosine-phosphorylated fragment spanning Tyr 985 of Ob-Rb was used to identify proteins that bind to this site. The SH2 domain containing protein tyrosine phosphatase 2 (SHP-2) was isolated from bovine and mouse hypothalamus by using this method. After cotransfection of Ob-Rb, Janus kinase 2 (JAK2), and SHP-2 into 293T cells, leptin results in direct binding of SHP-2 to the phosphorylated Tyr 985. The bound SHP-2 is itself tyrosine phosphorylated after leptin treatment. SHP-2 is not phosphorylated after leptin treatment when a Y-->F 985 receptor mutant is cotransfected. In the absence of SHP-2 phosphorylation, the level of JAK2 phosphorylation was increased. Tyrosyl phosphorylation of the leptin receptor and signal transducer and activater of transcription 3 (STAT3) are not affected by phosphorylation of SHP-2. These data suggest that activation of SHP-2 by the leptin receptor results in a decreased phosphorylation of JAK2 and may act to attenuate leptin signal transduction. The method used in this report can in principle be used to isolate additional components of the leptin, or other, signal transduction pathway. FAU - Li, C AU - Li C AD - Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY, USA. FAU - Friedman, J M AU - Friedman JM LA - eng PT - Journal Article PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Carrier Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Cell Surface) RN - 0 (Receptors, Leptin) RN - 0 (leptin receptor, mouse) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (Jak2 protein, mouse) RN - EC 2.7.10.2 (Janus Kinase 2) RN - EC 3.1.3.16 (Protein Phosphatase 2) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases) RN - EC 3.1.3.48 (Ptpn11 protein, mouse) RN - EC 3.1.3.48 (Ptpn6 protein, mouse) RN - EC 3.1.3.48 (SH2 Domain-Containing Protein Tyrosine Phosphatases) SB - IM MH - Amino Acid Sequence MH - Animals MH - Carrier Proteins/*metabolism MH - Cattle MH - Cell Line MH - Electrophoresis, Polyacrylamide Gel MH - Enzyme Activation MH - Intracellular Signaling Peptides and Proteins MH - Janus Kinase 2 MH - Mice MH - Molecular Sequence Data MH - Obesity/*physiopathology MH - Protein Phosphatase 2 MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11 MH - Protein Tyrosine Phosphatase, Non-Receptor Type 6 MH - Protein Tyrosine Phosphatases/*metabolism MH - Protein-Tyrosine Kinases/metabolism MH - *Proto-Oncogene Proteins MH - *Receptors, Cell Surface MH - Receptors, Leptin MH - SH2 Domain-Containing Protein Tyrosine Phosphatases MH - *Signal Transduction MH - Transfection MH - src Homology Domains PMC - PMC22269 EDAT- 1999/08/18 00:00 MHDA- 1999/08/18 00:01 CRDT- 1999/08/18 00:00 PHST- 1999/08/18 00:00 [pubmed] PHST- 1999/08/18 00:01 [medline] PHST- 1999/08/18 00:00 [entrez] AID - 10.1073/pnas.96.17.9677 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9677-82. doi: 10.1073/pnas.96.17.9677.