PMID:26063811

Citation	Shintani, T, Higashi, S, Takeuchi, Y, Gaudio, E, Trapasso, F, Fusco, A and Noda, M (2015) The R3 receptor-like protein tyrosine phosphatase subfamily inhibits insulin signalling by dephosphorylating the insulin receptor at specific sites. J. Biochem. 158:235-43
Abstract	The autophosphorylation of specific tyrosine residues occurs in the cytoplasmic region of the insulin receptor (IR) upon insulin binding, and this in turn initiates signal transduction. The R3 subfamily (Ptprb, Ptprh, Ptprj and Ptpro) of receptor-like protein tyrosine phosphatases (RPTPs) is characterized by an extracellular region with 6-17 fibronectin type III-like repeats and a cytoplasmic region with a single phosphatase domain. We herein identified the IR as a substrate for R3 RPTPs by using the substrate-trapping mutants of R3 RPTPs. The co-expression of R3 RPTPs with the IR in HEK293T cells suppressed insulin-induced tyrosine phosphorylation of the IR. In vitro assays using synthetic phosphopeptides revealed that R3 RPTPs preferentially dephosphorylated a particular phosphorylation site of the IR: Y960 in the juxtamembrane region and Y1146 in the activation loop. Among four R3 members, only Ptprj was co-expressed with the IR in major insulin target tissues, such as the skeletal muscle, liver and adipose tissue. Importantly, the activation of IR and Akt by insulin was enhanced, and glucose and insulin tolerance was improved in Ptprj-deficient mice. These results demonstrated Ptprj as a physiological enzyme that attenuates insulin signalling in vivo, and indicate that an inhibitor of Ptprj may be an insulin-sensitizing agent.
Links	PubMed Online version:10.1093/jb/mvv045
Keywords	Adipose Tissue/metabolism; Animals; Glucose/metabolism; HEK293 Cells; Humans; Insulin/metabolism; Liver/metabolism; Mice; Muscle, Skeletal/metabolism; Phosphorylation; Protein Tyrosine Phosphatases/genetics; Receptor, Insulin/biosynthesis; Receptor, Insulin/genetics; Receptor, Insulin/metabolism; Receptor-Like Protein Tyrosine Phosphatases, Class 3/biosynthesis; Receptor-Like Protein Tyrosine Phosphatases, Class 3/genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 3/metabolism; Signal Transduction; Tyrosine/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:PTPRJ		GO:0046627: negative regulation of insulin receptor signaling pathway	ECO:0000315:		P		Figure 4A: Mice with Ptprj expression knocked down show increased tyrosine phosphorylation of the insulin receptor in the presence of insulin. In addition, figure 4B shows that mice with Ptprj expression knocked down show increased activation via phosphorylation of Akt, a downstream effector of insulin signaling.	complete CACAO 12226
MOUSE:PTPRJ		GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	ECO:0000315:		P		Figure 4A: Mice with Ptprj expression knocked down show increased tyrosine phosphorylation of the insulin receptor (a member of the receptor protein tyrosine kinase superfamily) in the presence of insulin. In addition, figure 4B shows that mice with Ptprj expression knocked down show increased phosphorylation of Akt, a downstream effector of insulin signaling.	complete CACAO 12227
MOUSE:PTPRJ		GO:0042593: glucose homeostasis	ECO:0000315:		P		Figure 5A: Mice with Ptprj expression knocked down show decreased effect of injected glucose on blood glucose levels.	complete CACAO 12228
MOUSE:PTPRJ		GO:0035335: peptidyl-tyrosine dephosphorylation	ECO:0000315:		P		Figure 4A: Mice with Ptprj expression knocked down show increased tyrosine phosphorylation of the insulin receptor in the presence of insulin.	complete CACAO 12260
HUMAN:PTPRJ	Colocalizes with	GO:0005899: insulin receptor complex	ECO:0000314:		C		Figure 3C: Ptprj is shown by immunostaining to colocalize with the IR at the cell surface in HEK293T cells.	complete CACAO 12256
HUMAN:PTPRB		GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	ECO:0000314:		P		Figure 2B and 2C: Ptprb dephosphorylates tyrosine 1146 in the activation loop of the insulin receptor (a member of the receptor protein tyrosine kinase superfamily) in HEK293T (human embryonic kidney) cells	complete CACAO 12261
HUMAN:PTPRH		GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	ECO:0000314:		P		Figure 2B and 2C: Ptprh dephosphorylates tyrosine 1146 in the activation loop of the insulin receptor (a member of the receptor protein tyrosine kinase superfamily) in HEK293T (human embryonic kidney) cells	complete CACAO 12264
HUMAN:PTPRO		GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	ECO:0000314:		P		Figure 2B and 2C: Ptpro dephosphorylates tyrosine 1146 in the activation loop of the insulin receptor (a member of the receptor protein tyrosine kinase superfamily) in HEK293T (human embryonic kidney) cells	complete CACAO 12265
MOUSE:PTPRB		GO:0035335: peptidyl-tyrosine dephosphorylation	ECO:0000314:		P		Figure 1B: mouse Ptprb dephosphorylates tyrosine-phosphorylated IR in vitro	complete CACAO 12419
MOUSE:PTPRB		GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	ECO:0000314:		P		Figure 2B and 2C: mouse Ptprb dephosphorylates tyrosine 1146 in the activation loop of the insulin receptor (a member of the receptor protein tyrosine kinase superfamily) in HEK293T (human embryonic kidney) cells	complete CACAO 12420
MOUSE:PTPRH		GO:0035335: peptidyl-tyrosine dephosphorylation	ECO:0000314:		P		Figure 1B: mouse Ptprh dephosphorylates tyrosine-phosphorylated IR in vitro	complete CACAO 12417
MOUSE:PTPRH		GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	ECO:0000314:		P		Figure 2B and 2C: mouse Ptprh dephosphorylates tyrosine 1146 in the activation loop of the insulin receptor (a member of the receptor protein tyrosine kinase superfamily) in HEK293T (human embryonic kidney) cells	complete CACAO 12418
MOUSE:PTPRO		GO:0035335: peptidyl-tyrosine dephosphorylation	ECO:0000314:		P		Figure 1B: mouse Ptpro dephosphorylates tyrosine-phosphorylated IR in vitro	complete CACAO 12415
MOUSE:PTPRO		GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	ECO:0000314:		P		Figure 2B and 2C: mouse Ptpro dephosphorylates tyrosine 1146 in the activation loop of the insulin receptor (a member of the receptor protein tyrosine kinase superfamily) in HEK293T (human embryonic kidney) cells	complete CACAO 12416

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