Leptin signaling pathway (Bos taurus)

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OB-RSTAT1STAT1IP3PIP3PIP2ProteinDAGLeptin Signaling PathwaycAMPReceptorProteinProteinfood intakemRNASmall moleculeLigandRegulation ofPLCG2SHC1PJAK2PPLCG1RAF1PTIMP1GRB2NCOA1OBOB-RPPIK3R2PPIK3R1PSTAT3STAT3PSH2B1OBSP1KHDRBS1PSOCS7PTPN11PSOCS3ERBB2PKPNA4ESR1FYNPSRCPFOXO1PMTORPAKT1PRELAPCISHSOCS2IKBKGPCHUKPIKBKBPACACBPMAPK8PEIF4EPEIF4EBP1PSTAT5BPGSK3BPPTENPMAP2K2PMAP2K1PMAPK14PACACAPGSK3APBAXNOS3PPTK2PCFL2PRPS6PCREB1PPRKAA2PBADPRPS6KA1PIRS1PIRS1PSOS1HRASGTPMAPK1PMAPK3PSTAT3STAT3PPTPN1STAT3STAT1PSTAT3STAT1PSTAT1PSTAT1PESR1ESR1ESR1PDE3BRELAPNFKB1RELRELBCL2L1ELK1PAMPKPNA4PRPS6KB1PIL1RNIL1BPRKAA1PCREB1PCCND1JAK1PRHOAROCK1CDC42RAC1NFKB1CYNUCYNUCYNUROCK2CYNUCYNUCa2+ signalingPKC pathwayActin cytoskeletalreorganizationCYNUInduced activationEnzyme complexInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMolecule


Description

Leptin is a peptide hormone mainly synthesised and secreted from adipocytes. It is also expressed in other tissues including placenta, stomach and skeletal muscle. Leptin mediates its effects by binding to its receptor, leptin receptor (LEPR). LEPR belongs to gp130 family of cytokine receptor. LEPR is expressed in many tissues such as brain, adipose tissue, heart, placenta, lung and liver. Alternative splicing of LEPR results in six different isoforms, LEPRa, LEPRb, LEPRc, LEPRd, LEPRe and LEPRf. LEPRb is the longest isoform and possess signaling capacity. The role of other isoforms in leptin signaling is not clear. Leptin plays a major role in the regulation of energy homeostasis and regulate food intake and energy expenditure. Leptin is found to be transported to various regions of the brain across blood brain barrier. Impairment in leptin signaling across the blood brain barrier induces leptin resistance and thus obesity. Leptin is known to regulate reproduction, bone homeostasis and immune signaling. Leptin is also implicated in various physiological processers such as angiogenesis and hematopoiesis. LEPRb forms a homodimer and binds to leptin in 1:1 stoichiometry. This tetrameric receptor/ ligand complex appears to be essential for signaling. Leptin receptor lacks intrinsic kinase activity. It mediates multiple signaling pathways by binding to cytoplasmic kinases such as Janus Kinase 2 (JAK2). Activation of JAK2 by leptin promotes the tyrosine phosphorylation of LEPRb at Tyr-986, Try-1078 and Tyr-1141, thus activating LEPRb. Activation of leptin receptor with leptin activates signaling modules such as JAK/STAT, RAS/RAF/MAPK, IRS1/PI-3K, PLCĪ³ and AMPK/ACC modules. Tyrosine phosphorylation of LEPRb induces binding of STATs to LEPRb. Binding of STATs to the phosphorylated residues of LEPR leads to the JAK2 mediated tyrosine phosphorylation and activation of STATs. Activated STATs translocate to the nucleus and induces expression of genes such as suppressor of cytokine signaling 3 (SOCS3) and TIMP metallopeptidase inhibitor 1 (TIMP1). SOCS3 mediates feedback inhibition of leptin pathway by binding to Tyr-986 residue of LEPR. Cytosolic PTP1B also negatively regulates leptin pathway by dephosphorylating JAK2 and STAT3. Binding of leptin to its receptor results in the phosphorylation of PTPN1. Phosphorylated PTPN11 provides a docking site for GRB2, resulting in the activation of ERK module through RAS-RAF-MEK signaling. Leptin induces the activation of PI-3K by promoting the interaction and formation of SH2B/JAK2/IRS complex. Activation PI-3K mediates the activation of activation of protein kinases such as protein kinase B (AKT1) and downstream signaling cascades such as mammalian target of rapamycin (MTOR), nitric oxide synthase 3 (NOS3) and phosphodiesterase 3A, cGMP-inhibited (PDE3A). Activated AKT also regulates glycogen synthase kinase 3 alpha/beta (GSK3A/B) proteins. IkappaB kinases (IKKs) are activated in response to AKT activation. Activated IKKs induce nuclear translocation of NF-kappaB. Leptin also regulates 5'-AMP-activated protein kinase (AMPK) signaling. AMPK function as energy sensor and is activated in response to rise in AMP to ATP ratio. Activated AMPK regulate fatty acid biosymthesis by regulating the activity the enzyme, fatty acid biosynthesis-acetyl-CoA carboxylase (ACC). PLC gamma is activated in response to leptin signaling. Activated PLC gamma regulate intracellular calcium levels and also protein kinase C activation by hydrolysing phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).

Please access this pathway at NetSlim database.

If you use this pathway, you must cite following paper: Nanjappa, V., Raju, R., Muthusamy, B., Sharma, J., Thomas, J. K., Nidhina, P. A. H., Harsha, H. C., Pandey, A., Anilkumar G. and Prasad, T. S. K. (2011). A comprehensive curated reaction map of leptin signaling pathway. Journal of Proteomics and Bioinformatics. 4, 184-189.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP2034(80016) with a 94.0% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

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History

CompareRevisionActionTimeUserComment
89857view12:24, 6 October 2016MkutmonOntology Term : 'leptin system pathway' added !
89855view12:23, 6 October 2016MkutmonModified description
80927view15:31, 30 June 2015MkutmonNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACACAProtein
ACACBProteinENSBTAG00000022058 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:32
AKT1ProteinENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
BADProteinENSBTAG00000012511 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:572
BAXRnaENSBTAG00000013340 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:581
BCL2L1RnaENSBTAG00000006526 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:598
CCND1RnaENSBTAG00000017514 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:595
CDC42ProteinENSBTAG00000001700 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:998
CFL2ProteinENSBTAG00000015053 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1073
CHUKProteinENSBTAG00000007591 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
CISHProteinENSBTAG00000022622 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1154
CREB1ProteinENSBTAG00000005474 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1385
EIF4EBP1ProteinENSBTAG00000027654 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1978
EIF4EProteinENSBTAG00000009522 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1977
ELK1ProteinENSBTAG00000015817 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2002
ERBB2ProteinENSBTAG00000021798 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2064
ESR1ProteinENSBTAG00000007159 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2099
FOXO1ProteinENSBTAG00000044105 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2308
FYNProteinENSBTAG00000011851 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2534
GRB2ProteinENSBTAG00000004736 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2885
GSK3AProteinENSBTAG00000020756 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2931
GSK3BProteinENSBTAG00000048057 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2932
HRASProteinENSBTAG00000046644 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3265
IKBKBProteinENSBTAG00000007599 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
IKBKGProteinENSBTAG00000006268 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
IL1BRnaENSBTAG00000001321 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3553
IL1RNRnaENSBTAG00000019665 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3557
IRS1ProteinENSBTAG00000021308 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3667
JAK1ProteinENSBTAG00000003147 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3716
JAK2ProteinENSBTAG00000012047 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3717
KHDRBS1ProteinENSBTAG00000012497 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10657
KPNA4ProteinENSBTAG00000017416 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3840
MAP2K1ProteinENSBTAG00000033983 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
MAP2K2ProteinENSBTAG00000024450 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5605
MAPK14ProteinENSBTAG00000020783 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
MAPK1ProteinENSBTAG00000010312 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAPK3ProteinENSBTAG00000016156 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
MAPK8ProteinENSBTAG00000007876 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MTORProteinENSBTAG00000015325 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2475
NCOA1ProteinENSBTAG00000015007 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8648
NFKB1ProteinENSBTAG00000020270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
NOS3ProteinENSBTAG00000017680 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4846
OB-RProteinENSBTAG00000005910 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3953
OBProteinENSBTAG00000014911 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3952
PDE3BProteinENSBTAG00000005218 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5140
PIK3R1ProteinENSBTAG00000010989 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
PIK3R2ProteinHomologyConvert: Multiple homologues found: En:ENSBTAG00000002350;En:ENSBTAG00000002350;
PLCG1ProteinENSBTAG00000017584 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5335
PLCG2ProteinENSBTAG00000002103 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5336
PRKAA1ProteinENSBTAG00000000013 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5562
PRKAA2ProteinENSBTAG00000018747 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5563
PTENProtein
PTK2ProteinENSBTAG00000009578 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5747
PTPN11ProteinENSBTAG00000002048 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5781
PTPN1ProteinENSBTAG00000006616 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5770
RAC1ProteinENSBTAG00000009233 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
RAF1ProteinENSBTAG00000045748 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
RELAProteinENSBTAG00000013895 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
RELProteinENSBTAG00000015386 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5966
RHOAProteinENSBTAG00000004279 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:387
ROCK1ProteinENSBTAG00000008403 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6093
ROCK2ProteinENSBTAG00000005847 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9475
RPS6ProteinENSBTAG00000014449 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6194
RPS6KA1ProteinENSBTAG00000014447 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6195
RPS6KB1ProteinENSBTAG00000016851 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6198
SH2B1ProteinENSBTAG00000019219 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:25970
SHC1ProteinENSBTAG00000019838 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6464
SOCS2ProteinENSBTAG00000012007 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8835
SOCS3ProteinENSBTAG00000008441 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9021
SOCS7Protein
SOS1ProteinENSBTAG00000011643 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6654
SP1ProteinENSBTAG00000003021 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6667
SRCProteinENSBTAG00000008938 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6714
STAT1ProteinENSBTAG00000007867 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6772
STAT3ProteinENSBTAG00000021523 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6774
STAT5BProteinENSBTAG00000010125 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6777
TIMP1Rna

Annotated Interactions

No annotated interactions
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