Leptin signaling pathway (WP3274)

Bos taurus

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, PLCγ 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 [http://www.netpath.org/netslim/Leptin_pathway.html NetSlim] database. If you use this pathway, please cite the 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.

Authors

Martina Summer-Kutmon and Egon Willighagen

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

leptin system pathway

Participants

Label Type Compact URI Comment
OB-R Protein ensembl:ENSBTAG00000005910 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3953
STAT1 Protein ensembl:ENSBTAG00000007867 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6772
PLCG2 Protein ensembl:ENSBTAG00000002103 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5336
SHC1 Protein ensembl:ENSBTAG00000019838 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6464
JAK2 Protein ensembl:ENSBTAG00000012047 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3717
PLCG1 Protein ensembl:ENSBTAG00000017584 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5335
RAF1 Protein ensembl:ENSBTAG00000045748 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
GRB2 Protein ensembl:ENSBTAG00000004736 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2885
NCOA1 Protein ensembl:ENSBTAG00000015007 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8648
OB Protein ensembl:ENSBTAG00000014911 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3952
PIK3R1 Protein ensembl:ENSBTAG00000010989 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
STAT3 Protein ensembl:ENSBTAG00000021523 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6774
SH2B1 Protein ensembl:ENSBTAG00000019219 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:25970
SP1 Protein ensembl:ENSBTAG00000003021 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6667
KHDRBS1 Protein ensembl:ENSBTAG00000012497 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10657
PTPN11 Protein ensembl:ENSBTAG00000002048 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5781
SOCS3 Protein ensembl:ENSBTAG00000008441 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9021
ERBB2 Protein ensembl:ENSBTAG00000021798 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2064
KPNA4 Protein ensembl:ENSBTAG00000017416 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3840
ESR1 Protein ensembl:ENSBTAG00000007159 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2099
FYN Protein ensembl:ENSBTAG00000011851 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2534
SRC Protein ensembl:ENSBTAG00000008938 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6714
FOXO1 Protein ensembl:ENSBTAG00000044105 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2308
MTOR Protein ensembl:ENSBTAG00000015325 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2475
AKT1 Protein ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
RELA Protein ensembl:ENSBTAG00000013895 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
CISH Protein ensembl:ENSBTAG00000022622 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1154
SOCS2 Protein ensembl:ENSBTAG00000012007 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8835
IKBKG Protein ensembl:ENSBTAG00000006268 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
CHUK Protein ensembl:ENSBTAG00000007591 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
IKBKB Protein ensembl:ENSBTAG00000007599 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
ACACB Protein ensembl:ENSBTAG00000022058 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:32
MAPK8 Protein ensembl:ENSBTAG00000007876 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
EIF4E Protein ensembl:ENSBTAG00000009522 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1977
EIF4EBP1 Protein ensembl:ENSBTAG00000027654 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1978
STAT5B Protein ensembl:ENSBTAG00000010125 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6777
GSK3B Protein ensembl:ENSBTAG00000048057 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2932
MAP2K2 Protein ensembl:ENSBTAG00000024450 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5605
MAP2K1 Protein ensembl:ENSBTAG00000033983 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
MAPK14 Protein ensembl:ENSBTAG00000020783 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
GSK3A Protein ensembl:ENSBTAG00000020756 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2931
NOS3 Protein ensembl:ENSBTAG00000017680 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4846
PTK2 Protein ensembl:ENSBTAG00000009578 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5747
CFL2 Protein ensembl:ENSBTAG00000015053 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1073
RPS6 Protein ensembl:ENSBTAG00000014449 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6194
CREB1 Protein ensembl:ENSBTAG00000005474 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1385
PRKAA2 Protein ensembl:ENSBTAG00000018747 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5563
BAD Protein ensembl:ENSBTAG00000012511 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:572
RPS6KA1 Protein ensembl:ENSBTAG00000014447 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6195
IRS1 Protein ensembl:ENSBTAG00000021308 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3667
SOS1 Protein ensembl:ENSBTAG00000011643 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6654
HRAS Protein ensembl:ENSBTAG00000046644 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3265
MAPK1 Protein ensembl:ENSBTAG00000010312 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAPK3 Protein ensembl:ENSBTAG00000016156 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
PTPN1 Protein ensembl:ENSBTAG00000006616 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5770
PDE3B Protein ensembl:ENSBTAG00000005218 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5140
NFKB1 Protein ensembl:ENSBTAG00000020270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
REL Protein ensembl:ENSBTAG00000015386 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5966
ELK1 Protein ensembl:ENSBTAG00000015817 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2002
RPS6KB1 Protein ensembl:ENSBTAG00000016851 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6198
PRKAA1 Protein ensembl:ENSBTAG00000000013 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5562
JAK1 Protein ensembl:ENSBTAG00000003147 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3716
RHOA Protein ensembl:ENSBTAG00000004279 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:387
ROCK1 Protein ensembl:ENSBTAG00000008403 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6093
CDC42 Protein ensembl:ENSBTAG00000001700 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:998
RAC1 Protein ensembl:ENSBTAG00000009233 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
ROCK2 Protein ensembl:ENSBTAG00000005847 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9475

References

  1. NetPath: a public resource of curated signal transduction pathways. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia