id: MODULE:leptin_receptor_signaling title: Leptin receptor signaling — LepRb-JAK2 activation with SH2B1, STAT3 docking at pY1141, SHP2-ERK and SH2B1-IRS-PI3K branches, and SOCS3/PTP1B negative feedback; LEPR/JAK2/SH2B1/STAT3/PTPN11/IRS1/IRS2/SOCS3/PTPN1 description: >- The cell-intrinsic signalling unit of the long leptin receptor isoform (LepRb). Leptin binding brings receptor-associated JAK2 molecules together; JAK2, whose activity is potentiated by the SH2B1 adaptor, autophosphorylates and phosphorylates conserved tyrosines in the LepRb cytoplasmic tail. Phosphotyrosine 1141 (Tyr1138 in mouse) recruits STAT3, which JAK2 phosphorylates; STAT3 dimers enter the nucleus and drive leptin target genes, including SOCS3. Phosphotyrosine 986 (Tyr985 in mouse) recruits the phosphatase SHP2 (PTPN11), which is required for most leptin-induced ERK activation, while SH2B1 bound to JAK2 recruits IRS1 and IRS2 for JAK2 phosphorylation and activation of the PI3K-AKT branch. The response is terminated by STAT3-induced SOCS3, which docks on phosphotyrosine 986 and inhibits signalling, and by the ER-anchored phosphatase PTP1B (PTPN1), which dephosphorylates JAK2. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000363 title: leptin system pathway statement: >- RGD Pathway Ontology diagram from which this module is derived. Its genes are Lep, Lepr, Jak2, Stat3, Socs3, Ptpn1, Ptpn11, Sh2bpsm1 (SH2B1), Irs1 and Irs2; its edges are the Lepr-Jak2-Stat3 cascade, Socs3 and Ptpn1 inhibition of Jak2/Lepr/Stat3, Ptpn11 association with Lepr and Jak2, and Sh2b1 association with Jak2, Irs1 and Irs2, with links out to the Raf/Mek/Erk, Jak-Stat and PI3K-Akt pathways. - source_id: GO:0033210 title: leptin-mediated signaling pathway statement: >- The GO process that RGD cross-references from PW:0000363 and the concept of this module's root node: the series of molecular signals initiated by leptin binding to its receptor. - source_id: PMID:10799542 title: Activation of downstream signals by the long form of the leptin receptor. statement: >- Defines the two receptor phosphotyrosines and the branches they control: Tyr985 recruits SHP-2 and drives most ERK activation, Tyr1138 recruits STAT3 and drives SOCS3 induction. supporting_text: >- SHP-2 binding to Tyr(985) positively regulates the ERK --> c-fos pathway, and STAT3 binding to Tyr(1138) mediates the inhibitory SOCS3 pathway. - source_id: PMID:28270795 title: 'The Leptin Receptor Complex: Heavier Than Expected?' statement: >- Review of LepRb signalling used for the overall decomposition: three conserved tail tyrosines, STAT3, STAT5, SHP2-ERK and SH2B1-IRS branches, and SOCS3 feedback. supporting_text: >- ObRb contains three highly conserved tyrosine residues (Y985, Y1077, Y1138) required for efficient leptin signaling. notes: >- Derivation. This module is derived from RGD PW:0000363 (leptin system pathway; 11 RGD-curated human genes: INSR, IRS1, IRS2, JAK2, LEP, LEPR, PTPN1, PTPN11, SH2B1, SOCS3, STAT3). RGD's diagram and text describe the receptor-proximal JAK2-STAT3 cascade, the SHP2 (Ptpn11) route to Raf/Mek/Erk, the SH2B1-IRS route to PI3K-Akt, and SOCS3 and PTP1B negative regulation; all ten diagram genes are modelled here. INSR is on RGD's human gene list but not in the diagram or the RGD text, and the insulin receptor does no step of leptin receptor signalling; it is left out (insulin signalling is modules/insulin_receptor_signaling.yaml). The RGD description also opens with the hypothalamic POMC/AgRP/melanocortin axis; that physiology is not cell-intrinsic receptor signalling and is covered by the existing modules/leptin_melanocortin_signaling.yaml. Split with leptin_melanocortin_signaling. That module models the hypothalamic adipostat (leptin release, receptor activation, POMC processing, MC4R agonism, AGRP antagonism) and states in its notes that it deliberately compresses JAK2, STAT3, SOCS3 and PTP1B into the receptor's STAT output rather than re-modelling the cascade. This module is that missing cascade: what happens inside any LepRb-expressing cell (arcuate neurons, but also immune, endothelial and other peripheral cells) from receptor engagement to STAT3 transcription and its termination. The ligand step is included by module_ref to leptin_melanocortin_signaling#leptin_signal_generation rather than restated. The reverse link (this module's STAT3 output is what raises POMC and lowers AGRP transcription in arcuate neurons, i.e. the content of leptin_melanocortin_signaling#leptin_receptor_activation) is recorded here in prose because connections are document-scoped. Reuse of shared steps. STAT dimerisation and nuclear import, and STAT-dependent transcription, are the generic steps of modules/jak_stat_signaling.yaml and are included by module_ref (jak_stat_signaling#stat_dimerization_import, jak_stat_signaling#stat_transcription). The ERK relay and PI3K activation downstream of the two side branches are included by module_ref to erk_cascade#erk_relay and pi3k_akt_mtor#pi3k_activation. modules/il6_signaling.yaml was checked: its nodes are IL-6/gp130-specific (gp130 receptor engagement, gp130-associated JAKs, an IL-6 STAT3 output node) and expose no step that is genuinely shared with LepRb beyond the generic JAK-STAT trunk, so it is referenced in prose only; LepRb and gp130 are related class I cytokine receptors and both use STAT3 and SOCS3, but the docking sites and kinase (JAK2 only for LepRb) differ. Residue numbering. RGD and most primary papers use mouse LepRb numbering (Tyr985, Tyr1077, Tyr1138). In the human LEPR sequence (UniProt P48357, isoform B displayed) the equivalent residues are Tyr986, Tyr1079 and Tyr1141 (UniProt PTM and MUTAGEN lines). Descriptions here give human numbering with the mouse number in parentheses where a paper is quoted. STAT5. Leptin also activates STAT5 through pTyr1079 (mouse Tyr1077). STAT5 is not in the RGD diagram, and Y1077 mutant mice and STAT5 deletion in LepRb cells show only modest or no effect on energy balance (PMID:28270795), so STAT5 is recorded here and not modelled as a part. Substrate and target-gene rule. SOCS3 is both a STAT3 target gene and a participant: it is included as a participant only in the feedback step, where it does work (SH2 docking on pTyr986 and inhibition of JAK2), and the STAT3-to-SOCS3 relation is a POSITIVELY_REGULATES connection (induction), not a claim that SOCS3 takes part in STAT3 transcription. Other leptin STAT3 targets (POMC, AGRP repression) are outputs and are not participants. STAT3 is the substrate of JAK2 in the STAT3 docking step but also performs the transcription that is the pathway's output, so it is a participant by its own DNA-binding transcription factor activity. Functions and their support. Every annoton function comes from an experimental GOA row or the member gene review's core function: LEPR GO:0038021 (IDA), JAK2 GO:0004715 (IDA; JAK2 review core function), STAT3 GO:0000981 (IDA; STAT3 review), PTPN11 GO:0004726 (IDA; PTPN11 review), IRS1 and IRS2 GO:0035591 signaling adaptor activity (IDA; the IRS2 row is from the leptin paper PMID:15316008), SOCS3 GO:0004860 (IDA; SOCS3 review), PTPN1 GO:0004725 (IDA). Two functions are curator-authored without an experimental GOA row, because SH2B1 has no experimental MF annotation in human GOA and no gene review yet: protein tyrosine kinase activator activity (GO:0030296) for SH2B1 potentiation of JAK2, supported by PMID:10377387 (SH2-Bbeta stimulates JAK2 kinase activity about 20-fold) and PMID:28270795; and signaling adaptor activity (GO:0035591) for SH2B1 bridging JAK2 to IRS1/IRS2, supported by PMID:15316008 and consistent with the InterPro-based GOA row. Participants are grounded as GENE_PRODUCT UniProt accessions; no PANTHER family or PTN ids are asserted. GO-CAM. gocams/index.tsv contains no leptin-mediated signaling model. The seed's best GO-CAM lead (5f46c3b700002685, IL6:sIL6R trans-signaling) overlaps only through STAT3 and SOCS3 and is an IL-6 model, and the one LEP-containing model (6494e2e900002525) concerns SUCNR1 control of LEP expression; neither realises a step of this module, so no gocam_associations are recorded. module: id: leptin_receptor_signaling label: Leptin receptor (LepRb) intracellular signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: leptin-mediated signaling pathway term: id: GO:0033210 label: leptin-mediated signaling pathway description: >- From leptin binding to LepRb through JAK2 activation, receptor tyrosine phosphorylation, STAT3, SHP2-ERK and SH2B1-IRS-PI3K signalling, to SOCS3 and PTP1B termination. context: taxa: - preferred_term: mammals term: id: NCBITaxon:40674 label: Mammalia cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: leptin ligand supply node: id: leptin_ligand label: Leptin as the receptor ligand description: >- Included by reference to the leptin release step of the hypothalamic leptin-melanocortin module: adipocyte-derived leptin is the secreted ligand that engages LepRb. module_ref: leptin_melanocortin_signaling#leptin_signal_generation - order: 2 role: receptor engagement and JAK2 activation node: id: lepr_jak2_activation label: LepRb engagement, JAK2 activation and receptor tyrosine phosphorylation module_type: REGULATORY_STEP description: >- Leptin binding to the long receptor isoform LepRb assembles signalling-competent receptor complexes in which constitutively bound JAK2 molecules (box1/box2 region) trans-activate. JAK2 then phosphorylates the conserved LepRb tail tyrosines Tyr986, Tyr1079 and Tyr1141 (mouse Tyr985, Tyr1077, Tyr1138), creating docking sites for SH2 proteins. SH2B1 binds activated JAK2 and potentiates its kinase activity. The short receptor isoforms lack the tail tyrosines and do not activate STAT3. concepts: - preferred_term: leptin-mediated signaling pathway term: id: GO:0033210 label: leptin-mediated signaling pathway annotons: - id: lepr_receptor label: Leptin receptor long isoform (LepRb) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LEPR (isoform B, LepRb) term: id: UniProtKB:P48357 label: Leptin receptor function: preferred_term: leptin receptor activity term: id: GO:0038021 label: leptin receptor activity processes: - preferred_term: leptin-mediated signaling pathway term: id: GO:0033210 label: leptin-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Ligand-binding class I cytokine receptor that carries JAK2 and, once phosphorylated by it, presents the pTyr986 (SHP2, SOCS3) and pTyr1141 (STAT3) docking sites. evidence: - source_id: file:genes/human/LEPR/LEPR-uniprot.txt statement: >- UniProt PTM annotation: ligand-induced JAK2 phosphorylation of two conserved C-terminal tyrosines of isoform B, with Tyr-1141 needed for STAT3 and Tyr-986 for PTPN11 and SOCS3. supporting_text: >- Phosphorylation on Tyr-1141 is required for STAT3 binding/activation. - source_id: file:genes/human/LEPR/LEPR-ai-review.yaml statement: >- The LEPR gene review's core function is leptin receptor activity (GO:0038021) at the cell surface. - id: jak2_kinase label: JAK2 receptor-associated tyrosine kinase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK2 term: id: UniProtKB:O60674 label: Tyrosine-protein kinase JAK2 function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The only JAK used by LepRb; it autophosphorylates and phosphorylates the receptor tail, STAT3 and, via SH2B1, IRS1/IRS2. evidence: - source_id: PMID:10799542 statement: LepRb activation activates the associated JAK2 tyrosine kinase. supporting_text: >- Activation of LRb results in the activation of the associated Jak2 tyrosine kinase - source_id: file:genes/human/JAK2/JAK2-ai-review.yaml statement: >- The JAK2 gene review's core function is non-membrane spanning protein tyrosine kinase activity (GO:0004715) on cytokine receptor chains. - id: sh2b1_jak2_activator label: SH2B1 potentiation of JAK2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SH2B1 term: id: UniProtKB:Q9NRF2 label: SH2B adapter protein 1 function: preferred_term: protein tyrosine kinase activator activity term: id: GO:0030296 label: protein tyrosine kinase activator activity description: >- Curator-authored; SH2B1 has no experimental MF row in human GOA (see notes). locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- SH2-domain adaptor that binds phosphorylated JAK2 and raises its kinase activity, amplifying receptor, STAT3 and IRS phosphorylation; loss causes hyperphagic obesity in mice. evidence: - source_id: PMID:10377387 statement: >- SH2-Bbeta coexpressed with JAK2 stimulated JAK2 kinase activity about 20-fold, dependent on its SH2 domain (shown with growth hormone signalling). supporting_text: >- stimulated the kinase activity of JAK2 by approximately 20-fold - source_id: PMID:28270795 statement: In leptin signalling SH2B1 interacts with JAK2 and upregulates its kinase activity. supporting_text: >- Insulin receptor substrate 1, and particularly IRS2 are recruited to the ObRb via SH2B1, which interacts and upregulates the kinase activity of JAK2 - order: 3 role: STAT3 docking and tyrosine phosphorylation node: id: stat3_docking_phosphorylation label: STAT3 docking at pTyr1141 and JAK2 phosphorylation of STAT3 module_type: REGULATORY_STEP description: >- Latent cytoplasmic STAT3 binds phosphorylated Tyr1141 (mouse Tyr1138) through its SH2 domain and is phosphorylated by JAK2 on Tyr705. This is the step that commits the leptin signal to STAT3-dependent transcription. concepts: - preferred_term: tyrosine phosphorylation of STAT protein term: id: GO:0007260 label: tyrosine phosphorylation of STAT protein annotons: - id: stat3_transcription_factor label: STAT3 transcription factor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT3 term: id: UniProtKB:P40763 label: Signal transducer and activator of transcription 3 function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific processes: - preferred_term: leptin-mediated signaling pathway term: id: GO:0033210 label: leptin-mediated signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Recruited to the receptor as JAK2 substrate, then acts as the transcription factor of the leptin response, including induction of SOCS3. evidence: - source_id: PMID:11018044 statement: Phosphorylated mouse LepRb Tyr1138 binds STAT3 and mediates its phosphorylation and activation. supporting_text: >- Phosphorylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and transcriptional activation - source_id: file:genes/human/STAT3/STAT3-ai-review.yaml statement: >- The STAT3 gene review's core function is DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). - order: 4 role: STAT3 dimerization and nuclear import node: id: stat3_dimerization_import label: STAT3 dimerization and nuclear import description: >- Included by reference to the generic STAT dimerization and karyopherin import step of the canonical JAK-STAT module; nothing leptin-specific is added. module_ref: jak_stat_signaling#stat_dimerization_import - order: 5 role: STAT3 target-gene transcription node: id: stat3_target_transcription label: STAT3-dependent transcription of leptin target genes description: >- Included by reference to the STAT-dependent transcription step of the canonical JAK-STAT module. Leptin STAT3 targets include SOCS3 (the feedback inhibitor, next step) and, in arcuate neurons, POMC induction and AGRP repression, which are modelled in leptin_melanocortin_signaling. Target genes are outputs, not participants. module_ref: jak_stat_signaling#stat_transcription evidence: - source_id: PMID:10799542 statement: SOCS3 mRNA induction depends on Tyr1138-mediated STAT3 activation. supporting_text: SOCS3 mRNA accumulation requires Tyr(1138)-mediated STAT3 activation. - order: 6 role: SHP2-ERK branch from pTyr986 node: id: shp2_erk_branch label: SHP2 recruitment to pTyr986 and ERK activation module_type: REGULATORY_STEP description: >- Phosphorylated Tyr986 (mouse Tyr985) recruits SHP2 through its C-terminal SH2 domain. SHP2 is phosphorylated, binds GRB2 and, in a phosphatase-dependent manner, drives most leptin-induced ERK1/2 activation; the downstream RAF-MEK-ERK relay is the reusable ERK cascade. concepts: - preferred_term: positive regulation of ERK1 and ERK2 cascade term: id: GO:0070374 label: positive regulation of ERK1 and ERK2 cascade parts: - order: 1 role: SHP2 docking and activation node: id: shp2_docking label: SHP2 docking on pTyr986 module_type: REGULATORY_STEP annotons: - id: ptpn11_shp2 label: SHP2 tyrosine phosphatase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTPN11 (SHP2) term: id: UniProtKB:Q06124 label: Tyrosine-protein phosphatase non-receptor type 11 function: preferred_term: non-membrane spanning protein tyrosine phosphatase activity term: id: GO:0004726 label: non-membrane spanning protein tyrosine phosphatase activity processes: - preferred_term: positive regulation of ERK1 and ERK2 cascade term: id: GO:0070374 label: positive regulation of ERK1 and ERK2 cascade locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- SH2-recruited phosphatase whose catalytic activity and GRB2 binding couple the activated receptor to ERK activation. evidence: - source_id: PMID:28270795 statement: pY985 of mouse LepRb is the docking site for the C-terminal SH2 domain of SHP2. supporting_text: >- the pY985 motif serves as a docking site for the C-terminal SH2 domain of SHP2 - source_id: PMID:28270795 statement: SHP2 catalytic activity is needed for leptin-induced ERK activation. supporting_text: >- The phosphatase activity of SHP2 is necessary for leptin-mediated ERK activation - source_id: PMID:10799542 statement: Tyr985-recruited SHP-2 binds GRB2 and is required for most leptin-induced ERK activation. supporting_text: >- results in GRB-2 binding to tyrosine-phosphorylated SHP-2 and is required for the majority of ERK activation during LRb signaling - order: 2 role: RAF-MEK-ERK relay node: id: leptin_erk_relay label: RAF-MEK-ERK relay description: Included by reference to the ERK relay of the reusable ERK cascade module. module_ref: erk_cascade#erk_relay connections: - source: shp2_docking target: leptin_erk_relay connection_type: POSITIVELY_REGULATES description: SHP2 with GRB2 activates the RAS-RAF-MEK-ERK relay. - order: 7 role: SH2B1-IRS-PI3K branch node: id: sh2b1_irs_pi3k_branch label: SH2B1 recruitment of IRS1/IRS2 and PI3K activation module_type: REGULATORY_STEP description: >- SH2B1 bound to JAK2 also binds IRS1 and IRS2 through its PH and SH2 domains, forming a JAK2-SH2B1-IRS ternary complex in which JAK2 phosphorylates the IRS proteins; phospho-IRS recruits the p85 regulatory subunit of PI3K and activates AKT. The PI3K step itself is the reusable PI3K-AKT module. concepts: - preferred_term: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction term: id: GO:0051897 label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction parts: - order: 1 role: SH2B1 bridging of JAK2 to IRS proteins node: id: sh2b1_irs_recruitment label: SH2B1 bridges JAK2 to IRS1 and IRS2 module_type: REGULATORY_STEP annotons: - id: sh2b1_irs_adaptor label: SH2B1 adaptor bridging JAK2 and IRS participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SH2B1 term: id: UniProtKB:Q9NRF2 label: SH2B adapter protein 1 function: preferred_term: signaling adaptor activity term: id: GO:0035591 label: signaling adaptor activity description: >- Curator-authored from PMID:15316008; the only GOA MF row for SH2B1 with this term is InterPro-based (see notes). locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Brings IRS1/IRS2 to activated JAK2 for phosphorylation. evidence: - source_id: PMID:15316008 statement: SH2-B binds IRS1 and IRS2 and assembles a JAK2/SH2-B/IRS ternary complex in leptin signalling. supporting_text: >- mediated formation of a JAK2/SH2-B/IRS1 or IRS2 tertiary complex - id: irs1_adaptor label: IRS1 adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: IRS1 term: id: UniProtKB:P35568 label: Insulin receptor substrate 1 function: preferred_term: signaling adaptor activity term: id: GO:0035591 label: signaling adaptor activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- JAK2-phosphorylated docking protein that recruits the PI3K p85 subunit. evidence: - source_id: PMID:15316008 statement: >- SH2-B enhances leptin-stimulated IRS1/IRS2 tyrosine phosphorylation and their association with p85 and Akt activation. supporting_text: >- promoting association of IRS1 and IRS2 with the p85 regulatory subunit of PI 3-kinase and phosphorylation and activation of Akt - id: irs2_adaptor label: IRS2 adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: IRS2 term: id: UniProtKB:Q9Y4H2 label: Insulin receptor substrate 2 function: preferred_term: signaling adaptor activity term: id: GO:0035591 label: signaling adaptor activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- The IRS protein most strongly recruited to LepRb via SH2B1; recruits PI3K. evidence: - source_id: PMID:15316008 statement: IRS2, like IRS1, is recruited by SH2-B in response to leptin. supporting_text: >- promotes activation of the PI 3-kinase pathway by recruiting insulin receptor substrate 1 (IRS1) and IRS2 in response to leptin - order: 2 role: PI3K activation node: id: leptin_pi3k_activation label: PI3K activation description: Included by reference to the PI3K activation step of the reusable PI3K-AKT-mTOR module. module_ref: pi3k_akt_mtor#pi3k_activation connections: - source: sh2b1_irs_recruitment target: leptin_pi3k_activation connection_type: POSITIVELY_REGULATES description: Phospho-IRS1/IRS2 recruit and activate class IA PI3K. - order: 8 role: negative regulation and termination node: id: leptin_negative_regulation label: SOCS3 feedback and PTP1B dephosphorylation module_type: REGULATORY_STEP description: >- Two brakes act at the receptor-JAK2 level. STAT3-induced SOCS3 binds phosphorylated Tyr986 and inhibits JAK2, a delayed negative feedback loop. PTP1B (PTPN1), anchored on the cytoplasmic face of the endoplasmic reticulum, dephosphorylates JAK2 (and STAT3 in vitro), setting leptin sensitivity. concepts: - preferred_term: negative regulation of receptor signaling pathway via JAK-STAT term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT parts: - order: 1 role: SOCS3 feedback inhibition node: id: socs3_feedback label: SOCS3 feedback inhibition at pTyr986 module_type: REGULATORY_STEP annotons: - id: socs3_inhibitor label: SOCS3 feedback inhibitor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SOCS3 term: id: UniProtKB:O14543 label: Suppressor of cytokine signaling 3 function: preferred_term: protein kinase inhibitor activity term: id: GO:0004860 label: protein kinase inhibitor activity processes: - preferred_term: negative regulation of receptor signaling pathway via JAK-STAT term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Leptin-inducible SH2 protein that docks on pTyr986 of LepRb and inhibits JAK2-dependent signalling; a candidate mediator of leptin resistance. evidence: - source_id: PMID:11018044 statement: SOCS3 binds phosphorylated Tyr985 of mouse LepRb and needs it to inhibit receptor signalling. supporting_text: SOCS3 binds specifically to phosphorylated Tyr(985) of LRb - source_id: PMID:9660946 statement: Leptin induces hypothalamic SOCS-3, which blocks leptin signal transduction. supporting_text: >- SOCS-3 is a leptin-inducible inhibitor of leptin signaling - source_id: file:genes/human/SOCS3/SOCS3-ai-review.yaml statement: >- The SOCS3 gene review's core functions include protein kinase inhibitor activity (GO:0004860) on JAK kinases. - order: 2 role: PTP1B dephosphorylation of JAK2 node: id: ptp1b_dephosphorylation label: PTP1B dephosphorylation of JAK2 module_type: REACTION annotons: - id: ptpn1_ptp1b label: PTP1B tyrosine phosphatase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTPN1 (PTP1B) term: id: UniProtKB:P18031 label: Tyrosine-protein phosphatase non-receptor type 1 function: preferred_term: protein tyrosine phosphatase activity term: id: GO:0004725 label: protein tyrosine phosphatase activity processes: - preferred_term: negative regulation of receptor signaling pathway via JAK-STAT term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- Dephosphorylates activated JAK2 (and STAT3 in vitro); PTP1B-deficient mice are leptin-hypersensitive with enhanced hypothalamic STAT3 phosphorylation. evidence: - source_id: PMID:11970898 statement: PTP1B dephosphorylates JAK2 and restrains leptin signalling in vivo. supporting_text: >- PTP1B dephosphorylates the leptin receptor-associated kinase, Jak2 - source_id: PMID:15821101 statement: PTP1B directly dephosphorylates activated JAK2 and STAT3 in vitro. supporting_text: >- PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro connections: - source: leptin_ligand target: lepr_jak2_activation connection_type: CAUSES description: Leptin binding to LepRb activates receptor-associated JAK2. - source: lepr_jak2_activation target: stat3_docking_phosphorylation connection_type: CAUSES description: JAK2-phosphorylated Tyr1141 recruits STAT3, which JAK2 then phosphorylates. - source: stat3_docking_phosphorylation target: stat3_dimerization_import connection_type: PRECEDES description: Tyrosine-phosphorylated STAT3 leaves the receptor, dimerizes and enters the nucleus. - source: stat3_dimerization_import target: stat3_target_transcription connection_type: PRECEDES description: Nuclear STAT3 dimers bind target promoters. - source: lepr_jak2_activation target: shp2_erk_branch connection_type: CAUSES description: JAK2-phosphorylated Tyr986 recruits SHP2. - source: lepr_jak2_activation target: sh2b1_irs_pi3k_branch connection_type: CAUSES description: Activated JAK2 with bound SH2B1 recruits and phosphorylates IRS1/IRS2. - source: stat3_target_transcription target: socs3_feedback connection_type: POSITIVELY_REGULATES description: >- STAT3 induces SOCS3 transcription; this is gene induction of the inhibitor, not participation of SOCS3 in transcription. - source: socs3_feedback target: lepr_jak2_activation connection_type: NEGATIVELY_REGULATES description: SOCS3 bound at pTyr986 inhibits JAK2 signalling from the receptor. - source: ptp1b_dephosphorylation target: lepr_jak2_activation connection_type: NEGATIVELY_REGULATES description: PTP1B removes activating phosphates from JAK2. knowledge_gaps: - gap_statement: >- Which LepRb branch carries which physiological output in vivo is only partly resolved: mouse knock-in and deletion studies separate the Tyr1138-STAT3 arm (energy balance) from Tyr985, Tyr1077-STAT5 and SHP2-ERK arms, but the contribution of the SH2B1-IRS-PI3K arm, and whether SH2B1 acts mainly as a JAK2 activator or as an IRS adaptor in neurons, is not settled. gap_kind: - BIOLOGY - gap_statement: >- The relative weight of SOCS3 feedback and PTP1B dephosphorylation in diet-induced leptin resistance, and whether ER-anchored PTP1B reaches JAK2 at the plasma membrane or after receptor endocytosis, remain open. gap_kind: - BIOLOGY