LEPTIN SYSTEM PATHWAY (PW:0000363)
Description
The leptin system plays an essential role in energy homeostasis - the balance between energy intake and expenditure. Leptin acts on two classes of neurons: those expressing the appetite-decreasing peptides POMC and CART and those expressing the appetite-stimulating peptides NPY and AgRP, promoting the upregulation of the former and downregulation of the latter. The products of the Pomc and Agrp genes act on melanocortin receptors as agonists and antagonists, respectively and the leptin-melanocortin axis exerts a central role in the control of body weight. Leptin signaling occurs primarily via the Jak-Stat signaling pathway employing the Jak2-Stat3 combination. Leptin binding to its receptor, a single membrane- spanning protein with structural similarity to the class I cytokine receptor family, leads to receptor oligomerization, binding to and activation of Jak2. Jak2 activation involves autophosphorylation and phosphorylation of tyrosine residues on the cytoplasmic domain of the leptin receptor. P-Y1138 can then recruit Stat3 to the Lepr-Jak2 complex followed by Stat3 phosphorylation. P-Stat3 dimerizes and translocates to the nucleus where it regulates the transcription of target genes, including Socs3. Socs3 binding to P-Y985 on the leptin receptor and other sites within the Lepr-Jak2 complex provides a negative regulatory feedback loop. Inhibitory effects are also imparted by Ptpn1. In vitro, Ptpn1 dephophorylates both Jak2 and Stat3. Other pathways activated by leptin include phosphatidylinositol 3-kinase-Akt signaling via Jak2 activation of Irs (insulin receptor substrates) and the Raf/Mek/Erk module of MAPK cascades via Ptpn11 acting upstream of the two pathways, respectively. It has been shown that Sh2bpsm1 - a protein containing both PH and SH2 (
plekstrin and
src homology 2 domains) - can recruit Irs1 and Irs2 in response to leptin, form a ternary complex with Irs1 or Irs2 and activate Jak2 to promote tyrosine phopshorylation of Irs proteins by Jak2. It is worth mentioning that Stat and Socs proteins as well as Ptpn11 contain SH2 -
src homology 2 - domains that bind to phosphotyrosine-containing targets. Ptpn11, acting upstream of the ERK1/2 pathway, can interact with either phosphorylated leptin receptor or Jak2.
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GO:0033210 ]
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Pathway Diagram:
Genes in Pathway:
G
Irs1 insulin receptor substrate 1
ISO RGD
PMID:15316008 RGD:2302071
NCBI chr 9:83,552,964...83,605,797
G
Irs2 insulin receptor substrate 2
ISO RGD
PMID:15316008 RGD:2302071
NCBI chr16:78,488,249...78,512,482
G
Jak2 Janus kinase 2
ISO RGD
PMID:17010638 PMID:15316008 RGD:1625125 , RGD:2302071
NCBI chr 1:226,995,334...227,054,381
G
Lep leptin
TAS IDA ISO RGD
PMID:11102451 PMID:9618284 PMID:9070213 PMID:17010638 RGD:61790 , RGD:2290294 , RGD:2290293 , RGD:1625125
NCBI chr 4:57,661,127...57,675,262
G
Lepr leptin receptor
TAS IDA ISO RGD
PMID:11102451 PMID:9618284 PMID:9070213 PMID:17010638 PMID:17229951 RGD:61790 , RGD:2290294 , RGD:2290293 , RGD:1625125 , RGD:1600611
NCBI chr 5:116,294,409...116,477,904
G
Lepr_v1 leptin receptor, variant 1
IDA RGD
PMID:9070213 PMID:9618284 RGD:2290293 , RGD:2290294
G
Lepr_v2 leptin receptor, variant 2
ISO IDA RGD
PMID:17578380 PMID:9618284 PMID:9070213 RGD:2290292 , RGD:2290294 , RGD:2290293
G
Ptpn1 protein tyrosine phosphatase, non-receptor type 1
ISO RGD
PMID:15821101 RGD:2289366
NCBI chr 3:156,638,811...156,687,503
G
Ptpn11 protein tyrosine phosphatase, non-receptor type 11
ISO RGD
PMID:17872473 RGD:2289807
NCBI chr12:35,365,436...35,424,925
G
Sh2b1 SH2B adaptor protein 1
ISO RGD
PMID:15316008 RGD:2302071
NCBI chr 1:181,048,622...181,057,036
G
Socs3 suppressor of cytokine signaling 3
ISO RGD
PMID:17010638 RGD:1625125
NCBI chr10:103,193,909...103,197,322
G
Stat3 signal transducer and activator of transcription 3
ISO RGD
PMID:17229951 PMID:17010638 RGD:1600611 , RGD:1625125
NCBI chr10:85,811,206...85,863,057
G
Insr insulin receptor
IMP increased basal hypothalamic leptin signaling without changes in leptin receptor expression after antisense-mediated hypothalamus-specific Insr knock-down
RGD
PMID:17585961 RGD:2290473
NCBI chr12:1,193,193...1,330,976
G
Lep leptin
TAS RGD
PMID:11102451 RGD:61790
NCBI chr 4:57,661,127...57,675,262
G
Lepr leptin receptor
TAS ISO RGD
PMID:11102451 PMID:17229951 RGD:61790 , RGD:1600611
NCBI chr 5:116,294,409...116,477,904
G
Lepr_v2 leptin receptor, variant 2
ISO RGD
PMID:17578380 RGD:2290292
Pathway Gene Annotations
Disease Annotations Associated with Genes in the leptin system pathway
Irs1 AIDS Dementia Complex , Alzheimer's disease , coronary artery disease , Coronary Disease , diabetes mellitus , end stage renal disease , Endotoxemia , Experimental Diabetes Mellitus , familial hyperlipidemia , Fetal Growth Retardation , head and neck squamous cell carcinoma , hepatocellular carcinoma , hyperinsulinism , Insulin Resistance , maturity-onset diabetes of the young type 1 , metabolic dysfunction-associated steatotic liver disease , Metabolic Syndrome , Neoplastic Cell Transformation , obesity , osteoporosis , pre-malignant neoplasm , Prostatic Neoplasms , Sepsis , type 2 diabetes mellitus , uterine fibroid Irs2 Alzheimer's disease , Anal Atresia, Hypospadias, and Penoscrotal Inversion , Diabetic Nephropathies , Experimental Diabetes Mellitus , factor X deficiency , Fetal Growth Retardation , hepatocellular carcinoma , hyperglycemia , Insulin Resistance , maturity-onset diabetes of the young type 1 , medulloblastoma , metabolic dysfunction-associated steatotic liver disease , Metabolic Syndrome , obesity , osteoporosis , Stomach Neoplasms , type 2 diabetes mellitus Jak2 acute kidney failure , Acute Lymphoblastic Leukemia, with Lymphomatous Features , acute myeloid leukemia , adrenocortical carcinoma , alcoholic liver cirrhosis , Alzheimer's disease , anemia , ankylosing spondylitis , atherosclerosis , bacterial gastritis , Brain Injuries , Budd-Chiari syndrome , Cachexia , calcinosis , Cancer Pain , chromosome 9p deletion syndrome , chronic myelogenous leukemia, BCR-ABL1 positive , chronic myeloid leukemia , colon adenocarcinoma , colon cancer , colorectal carcinoma , COVID-19 , Crohn's disease , Diabetic Nephropathies , esophageal carcinoma , esophagus squamous cell carcinoma , essential thrombocythemia , Experimental Arthritis , Experimental Autoimmune Encephalomyelitis , Experimental Colitis , Experimental Liver Cirrhosis , Experimental Liver Neoplasms , familial erythrocytosis 1 , familial erythrocytosis 2 , genetic disease , Genetic Predisposition to Disease , glucose intolerance , Growth Disorders , heart disease , heart valve disease , hepatocellular carcinoma , hereditary breast ovarian cancer syndrome , Hereditary Neoplastic Syndromes , Hyperalgesia , hyperuricemia , Inflammation , Intestinal Reperfusion Injury , leukemia , limited scleroderma , liver cancer , liver cirrhosis , Liver Injury , Liver Reperfusion Injury , lung adenocarcinoma , lung carcinoma , lung non-small cell carcinoma , mesenteric vascular occlusion , metabolic dysfunction-associated steatohepatitis , metabolic dysfunction-associated steatotic liver disease , myelofibrosis , myeloid neoplasm , myeloproliferative neoplasm , myocardial infarction , Myocardial Ischemia , Myocardial Reperfusion Injury , nasopharynx carcinoma , Neoplasm Metastasis , Neoplastic Cell Transformation , nephrotic syndrome , Niemann-Pick disease type C1 , obesity , polycythemia , polycythemia vera , portal hypertension , Pregnancy Complications , primary biliary cholangitis , primary ovarian insufficiency , Prostatic Neoplasms , Reperfusion Injury , retinal detachment , rheumatoid arthritis , scrapie , Sepsis , Sepsis-Associated Encephalopathy , Spinal Cord Injuries , Splenomegaly , Spontaneous Abortions , steatotic liver disease , stomach cancer , Stroke , systemic lupus erythematosus , Thrombocythemia 3 , thrombocytosis , Thromboembolism , thrombosis , transient cerebral ischemia , ulcerative colitis , urinary bladder cancer , Uterine Cervical Neoplasms , Venous Thrombosis Lep abdominal obesity-metabolic syndrome , abdominal obesity-metabolic syndrome 1 , acute pancreatitis , acute promyelocytic leukemia , adult respiratory distress syndrome , alcohol dependence , alcoholic liver cirrhosis , Alzheimer's disease , asthma , autistic disorder , autoimmune hepatitis , bacterial pneumonia , Body Weight Changes , Brain Injuries , breast cancer , Breast Neoplasms , Choroidal Neovascularization , Chronic Hepatitis C , chronic obstructive pulmonary disease , Colonic Neoplasms , congenital leptin deficiency , congestive heart failure , Crohn's disease , cystic fibrosis , diabetes mellitus , Diabetic Nephropathies , Dyslipidemias , End Stage Liver Disease , end stage renal disease , Experimental Arthritis , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Experimental Mammary Neoplasms , familial hyperlipidemia , Female Infertility , Femoral Fractures , Fetal Growth Retardation , gastric ulcer , gestational diabetes , glucose intolerance , hepatocellular carcinoma , hepatocellular clear cell carcinoma , Hepatomegaly , heroin dependence , Huntington's disease , Hypercapnia , Hypercholesterolemia , hyperglycemia , hyperinsulinism , Hyperphagia , Hyperplasia , hypertension , Hypertriglyceridemia , hypogonadism , Hypoventilation , Inflammation , Insulin Resistance , Kidney Reperfusion Injury , Knee Osteoarthritis , lipid metabolism disorder , lung disease , lung non-small cell carcinoma , metabolic dysfunction-associated steatotic liver disease , Metabolic Syndrome , morbid obesity , Myocardial Reperfusion Injury , Nerve Degeneration , obesity , obstructive sleep apnea , Oral Ulcer , osteoarthritis , osteoporosis , Parkinson's disease , pleomorphic xanthoastrocytoma , Pneumococcal Pneumonia , polycystic ovary syndrome , Polydipsia , Polyuria , pre-eclampsia , primary biliary cholangitis , Prostatic Neoplasms , proteinuria , renal cell carcinoma , Reperfusion Injury , rhinitis , Sepsis , short bowel syndrome , Spinal Cord Injuries , steatotic liver disease , Tachycardia , type 2 diabetes mellitus , Weight Gain , Weight Loss Lepr Albuminuria , Animal Disease Models , arteriosclerosis , bone disease , Breast Neoplasms , cardiomyopathy , Chronic Hepatitis B , Chronic Hepatitis C , chronic kidney disease , chronic obstructive pulmonary disease , cognitive disorder , congenital disorder of glycosylation It , congenital leptin deficiency , congestive heart failure , coronary artery disease , Coronary Disease , Delayed Puberty , diabetes mellitus , Diabetic Cardiomyopathies , Diabetic Nephropathies , diabetic neuropathy , Diastolic Dysfunction , diastolic heart failure , dilated cardiomyopathy , Dyslipidemias , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , familial hyperlipidemia , Female Infertility , Fibrosis , genetic disease , gestational diabetes , Gliosis , glucose intolerance , granulosa cell tumor , hepatocellular carcinoma , hepatocellular clear cell carcinoma , Hepatomegaly , human immunodeficiency virus infectious disease , Hyperalgesia , hyperglycemia , hyperinsulinism , Hyperphagia , hypertension , hypogonadism , infertility , inherited metabolic disorder , Insulin Resistance , intellectual disability , kidney disease , kidney failure , Knee Osteoarthritis , Left Ventricular Hypertrophy , Leptin Receptor Deficiency , metabolic dysfunction-associated steatohepatitis , metabolic dysfunction-associated steatotic liver disease , Metabolic Syndrome , morbid obesity , Myocardial Ischemia , Myocardial Reperfusion Injury , Nasal Polyps , nephritis , obesity , obstructive sleep apnea , osteoporosis , Overweight , pancreas disease , pancreatitis , pituitary gland disease , Pneumococcal Pneumonia , pre-eclampsia , Precocious Puberty , primary biliary cholangitis , primary immunodeficiency disease , primary ovarian insufficiency , proteinuria , pulmonary fibrosis , pulmonary hypertension , renal fibrosis , Respiratory Tract Infections , Right Ventricular Hypertrophy , short bowel syndrome , sleep apnea , Spinal Fractures , steatotic liver disease , type 2 diabetes mellitus , Varicose Ulcer , Ventricular Dysfunction, Left , Weight Gain Ptpn1 B-cell lymphoma , Calcification of Aortic Valve , Carotid Artery Injuries , coronary artery disease , diabetes mellitus , essential hypertension , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Hodgkin's lymphoma , hyperinsulinism , hypertension , Inflammation , Insulin Resistance , limb ischemia , Mediastinal Neoplasms , obesity , proliferative diabetic retinopathy , Rett syndrome , Stroke , type 2 diabetes mellitus , Wounds and Injuries Ptpn11 acute myeloid leukemia , acute promyelocytic leukemia , adenocarcinoma , anogenital venereal wart , aortic valve stenosis , arrhythmogenic right ventricular cardiomyopathy , atrial heart septal defect 1 , atrophic gastritis , autism spectrum disorder , B-Cell Chronic Lymphocytic Leukemia , Brain Neoplasms , Cafe-au-Lait Spots , cancer , cardiofaciocutaneous syndrome , cardiomyopathy , Cardiovascular Abnormalities , Carotid Artery Injuries , cervical cancer , chondroma , chronic lymphocytic leukemia , Colorectal Neoplasms , Costello syndrome , craniosynostosis , Developmental Disabilities , dilated cardiomyopathy , disease of metabolism , Duane retraction syndrome , Dwarfism , embryonal rhabdomyosarcoma , Experimental Leukemia , Failure to Thrive , Fetal Growth Retardation , Funnel Chest , gastric adenocarcinoma , genetic disease , glaucoma , Haemophilus Infections , Helicobacter Infections , hemorrhagic disease , hepatocellular adenoma , hereditary multiple exostoses , Hereditary Neoplastic Syndromes , high grade glioma , Hydrops Fetalis , hypertrophic cardiomyopathy , idiopathic scoliosis , influenza , intellectual disability , juvenile myelomonocytic leukemia , learning disability , leukemia , long QT syndrome , long QT syndrome 1 , lung adenocarcinoma , lung squamous cell carcinoma , lymphoma , malignant astrocytoma , metachondromatosis , microcephaly , multiple myeloma , myeloid leukemia associated with Down Syndrome , neuroblastoma , Neurodevelopmental Disorders , neurofibroma , neurofibromatosis-Noonan syndrome , Noonan Like Syndrome , Noonan syndrome , Noonan syndrome 1 , Noonan syndrome 3 , Noonan syndrome with multiple lentigines , Noonan syndrome with multiple lentigines 1 , Noonan Syndrome-Like Disorder with or without Juvenile Myelomonocytic Leukemia , Ollier disease , Osteochondroma , Paraproteinemias , patent ductus arteriosus , patent foramen ovale , plasma cell neoplasm , ptosis , RASopathy , Right Ventricular Hypertrophy , Romano-Ward Syndrome , scoliosis , spermatogenic failure 57 , squamous cell carcinoma , Staphylococcal Pneumonia , stomach cancer , strabismus , T-cell acute lymphoblastic leukemia , tetralogy of Fallot , thrombocytopenia , tricuspid valve insufficiency , Ventricular Premature Complexes , Ventricular Tachycardia , Werner syndrome Sh2b1 Brody myopathy , chromosome 16p11.2 deletion syndrome, 220-kb , chromosome 16p11.2 deletion syndrome, 593-kb , neuronal ceroid lipofuscinosis , obesity , Primary Ovarian Failure , primary ovarian insufficiency , schizophrenia Socs3 atherosclerosis , Burns , cholangiocarcinoma , ductal carcinoma in situ , Endometrial Neoplasms , Endotoxemia , Experimental Arthritis , Experimental Colitis , Experimental Diabetes Mellitus , Experimental Mammary Neoplasms , Fibrosis , Helicobacter Infections , hepatocellular carcinoma , human immunodeficiency virus infectious disease , Hypertriglyceridemia , idiopathic generalized epilepsy , Insulin Resistance , invasive ductal carcinoma , liver disease , Lymphatic Metastasis , Myocardial Ischemia , obesity , Reperfusion Injury , Sepsis , status epilepticus , steatotic liver disease , type 2 diabetes mellitus Stat3 acute myeloid leukemia , adenocarcinoma , adenoid cystic carcinoma , adult T-cell leukemia/lymphoma , Alzheimer's disease , anaplastic large cell lymphoma , angiomyolipoma , angiosarcoma , Animal Disease Models , Animal Mammary Neoplasms , atherosclerosis , Atrophy , autistic disorder , autoimmune disease , B-lymphoblastic leukemia/lymphoma , bacterial pneumonia , Behcet's disease , Brain Injuries , brain ischemia , breast cancer , Breast Neoplasms , carcinoma , Cardiomegaly , cardiomyopathy , cervix uteri carcinoma in situ , Chemical and Drug Induced Liver Injury , Choroidal Neovascularization , Chronic Hepatitis , Chronic Hepatitis C , chronic lymphocytic leukemia , Churg-Strauss syndrome , colon adenocarcinoma , colon cancer , Colonic Neoplasms , colorectal cancer , colorectal carcinoma , congenital diaphragmatic hernia , congestive heart failure , Copper-Overload Cirrhosis , Crohn's disease , depressive disorder , Diabetic Nephropathies , diffuse large B-cell lymphoma , duodenal ulcer , Endometrial Neoplasms , Epidermal Hyperplasia , esophageal carcinoma , Experimental Arthritis , Experimental Autoimmune Encephalomyelitis , Experimental Autoimmune Uveitis , Experimental Autoimmune Uveoretinitis , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Experimental Liver Neoplasms , Experimental Mammary Neoplasms , Experimental Neoplasms , Fever , Fibrosis , follicular dendritic cell sarcoma , gastric adenocarcinoma , genetic disease , glioblastoma , growth hormone insensitivity syndrome with immune dysregulation 1 , head and neck squamous cell carcinoma , heart disease , hepatocellular carcinoma , hyper IgE recurrent infection syndrome 1 , hyper IgE syndrome , Hyperalgesia , hyperuricemia , idiopathic pulmonary fibrosis , Inflammation , inflammatory bowel disease , irritant dermatitis , juvenile rheumatoid arthritis , liver cirrhosis , Liver Injury , Liver Neoplasms , Lung Neoplasms , lung non-small cell carcinoma , lymphangioleiomyomatosis , Lymphatic Metastasis , lymphoproliferative syndrome , medulloblastoma , Memory Disorders , metabolic dysfunction-associated steatotic liver disease , middle cerebral artery infarction , Multisystem Autoimmune Disease, Infantile-Onset, 1 , Myocardial Reperfusion Injury , Nasal Polyps , nasal type extranodal NK/T-cell lymphoma , nasopharynx carcinoma , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplastic Cell Transformation , nephroblastoma , neutropenia , Niemann-Pick disease type C1 , obesity , ovarian cancer , Ovarian Neoplasms , Oxygen-Induced Retinopathy , pancreatic cancer , periodontitis , peripartum cardiomyopathy , pre-malignant neoplasm , primary immunodeficiency disease , prostate cancer , prostate carcinoma , Prostatic Neoplasms , psoriasis , psoriatic arthritis , pulmonary fibrosis , pulmonary hypertension , Pulmonary Hypertension, Hypoxia-Induced , Pyogenic Granuloma , rectum adenocarcinoma , renal cell carcinoma , Reperfusion Injury , Retina Reperfusion Injury , rheumatoid arthritis , scrapie , Sepsis , Sepsis-Associated Encephalopathy , skin melanoma , Skin Neoplasms , squamous cell carcinoma , stomach cancer , Stomach Neoplasms , Subarachnoid Hemorrhage , T-cell acute lymphoblastic leukemia , T-cell non-Hodgkin lymphoma , Tongue Neoplasms , transient cerebral ischemia , type 1 diabetes mellitus , type 2 diabetes mellitus , ulcerative colitis , urinary bladder cancer , Uterine Cervical Neoplasms
abdominal obesity-metabolic syndrome Lep abdominal obesity-metabolic syndrome 1 Lep acute kidney failure Jak2 Acute Lymphoblastic Leukemia, with Lymphomatous Features Jak2 acute myeloid leukemia Jak2 , Ptpn11 , Stat3 acute pancreatitis Lep acute promyelocytic leukemia Lep , Ptpn11 adenocarcinoma Ptpn11 , Stat3 adenoid cystic carcinoma Stat3 adrenocortical carcinoma Jak2 adult respiratory distress syndrome Lep adult T-cell leukemia/lymphoma Stat3 AIDS Dementia Complex Irs1 Albuminuria Lepr alcohol dependence Lep alcoholic liver cirrhosis Jak2 , Lep Alzheimer's disease Irs1 , Irs2 , Jak2 , Lep , Stat3 Anal Atresia, Hypospadias, and Penoscrotal Inversion Irs2 anaplastic large cell lymphoma Stat3 anemia Jak2 angiomyolipoma Stat3 angiosarcoma Stat3 Animal Disease Models Lepr , Stat3 Animal Mammary Neoplasms Stat3 ankylosing spondylitis Jak2 anogenital venereal wart Ptpn11 aortic valve stenosis Ptpn11 arrhythmogenic right ventricular cardiomyopathy Ptpn11 arteriosclerosis Lepr asthma Lep atherosclerosis Jak2 , Socs3 , Stat3 atrial heart septal defect 1 Ptpn11 atrophic gastritis Ptpn11 Atrophy Stat3 autism spectrum disorder Ptpn11 autistic disorder Lep , Stat3 autoimmune disease Stat3 autoimmune hepatitis Lep B-Cell Chronic Lymphocytic Leukemia Ptpn11 B-cell lymphoma Ptpn1 B-lymphoblastic leukemia/lymphoma Stat3 bacterial gastritis Jak2 bacterial pneumonia Lep , Stat3 Behcet's disease Stat3 Body Weight Changes Lep bone disease Lepr Brain Injuries Jak2 , Lep , Stat3 brain ischemia Stat3 Brain Neoplasms Ptpn11 breast cancer Lep , Stat3 Breast Neoplasms Lep , Lepr , Stat3 Brody myopathy Sh2b1 Budd-Chiari syndrome Jak2 Burns Socs3 Cachexia Jak2 Cafe-au-Lait Spots Ptpn11 Calcification of Aortic Valve Ptpn1 calcinosis Jak2 cancer Ptpn11 Cancer Pain Jak2 carcinoma Stat3 cardiofaciocutaneous syndrome Ptpn11 Cardiomegaly Stat3 cardiomyopathy Lepr , Ptpn11 , Stat3 Cardiovascular Abnormalities Ptpn11 Carotid Artery Injuries Ptpn1 , Ptpn11 cervical cancer Ptpn11 cervix uteri carcinoma in situ Stat3 Chemical and Drug Induced Liver Injury Stat3 cholangiocarcinoma Socs3 chondroma Ptpn11 Choroidal Neovascularization Lep , Stat3 chromosome 16p11.2 deletion syndrome, 220-kb Sh2b1 chromosome 16p11.2 deletion syndrome, 593-kb Sh2b1 chromosome 9p deletion syndrome Jak2 Chronic Hepatitis Stat3 Chronic Hepatitis B Lepr Chronic Hepatitis C Lep , Lepr , Stat3 chronic kidney disease Lepr chronic lymphocytic leukemia Ptpn11 , Stat3 chronic myelogenous leukemia, BCR-ABL1 positive Jak2 chronic myeloid leukemia Jak2 chronic obstructive pulmonary disease Lep , Lepr Churg-Strauss syndrome Stat3 cognitive disorder Lepr colon adenocarcinoma Jak2 , Stat3 colon cancer Jak2 , Stat3 Colonic Neoplasms Lep , Stat3 colorectal cancer Stat3 colorectal carcinoma Jak2 , Stat3 Colorectal Neoplasms Ptpn11 congenital diaphragmatic hernia Stat3 congenital disorder of glycosylation It Lepr congenital leptin deficiency Lep , Lepr congestive heart failure Lep , Lepr , Stat3 Copper-Overload Cirrhosis Stat3 coronary artery disease Irs1 , Lepr , Ptpn1 Coronary Disease Irs1 , Lepr Costello syndrome Ptpn11 COVID-19 Jak2 craniosynostosis Ptpn11 Crohn's disease Jak2 , Lep , Stat3 cystic fibrosis Lep Delayed Puberty Lepr depressive disorder Stat3 Developmental Disabilities Ptpn11 diabetes mellitus Irs1 , Lep , Lepr , Ptpn1 Diabetic Cardiomyopathies Lepr Diabetic Nephropathies Irs2 , Jak2 , Lep , Lepr , Stat3 diabetic neuropathy Lepr Diastolic Dysfunction Lepr diastolic heart failure Lepr diffuse large B-cell lymphoma Stat3 dilated cardiomyopathy Lepr , Ptpn11 disease of metabolism Ptpn11 Duane retraction syndrome Ptpn11 ductal carcinoma in situ Socs3 duodenal ulcer Stat3 Dwarfism Ptpn11 Dyslipidemias Lep , Lepr embryonal rhabdomyosarcoma Ptpn11 End Stage Liver Disease Lep end stage renal disease Irs1 , Lep Endometrial Neoplasms Socs3 , Stat3 Endotoxemia Irs1 , Socs3 Epidermal Hyperplasia Stat3 esophageal carcinoma Jak2 , Stat3 esophagus squamous cell carcinoma Jak2 essential hypertension Ptpn1 essential thrombocythemia Jak2 Experimental Arthritis Jak2 , Lep , Socs3 , Stat3 Experimental Autoimmune Encephalomyelitis Jak2 , Stat3 Experimental Autoimmune Uveitis Stat3 Experimental Autoimmune Uveoretinitis Stat3 Experimental Colitis Jak2 , Socs3 Experimental Diabetes Mellitus Irs1 , Irs2 , Lep , Lepr , Ptpn1 , Socs3 , Stat3 Experimental Leukemia Ptpn11 Experimental Liver Cirrhosis Jak2 , Lep , Lepr , Ptpn1 , Stat3 Experimental Liver Neoplasms Jak2 , Stat3 Experimental Mammary Neoplasms Lep , Socs3 , Stat3 Experimental Neoplasms Stat3 factor X deficiency Irs2 Failure to Thrive Ptpn11 familial erythrocytosis 1 Jak2 familial erythrocytosis 2 Jak2 familial hyperlipidemia Irs1 , Lep , Lepr Female Infertility Lep , Lepr Femoral Fractures Lep Fetal Growth Retardation Irs1 , Irs2 , Lep , Ptpn11 Fever Stat3 Fibrosis Lepr , Socs3 , Stat3 follicular dendritic cell sarcoma Stat3 Funnel Chest Ptpn11 gastric adenocarcinoma Ptpn11 , Stat3 gastric ulcer Lep genetic disease Jak2 , Lepr , Ptpn11 , Stat3 Genetic Predisposition to Disease Jak2 gestational diabetes Lep , Lepr glaucoma Ptpn11 glioblastoma Stat3 Gliosis Lepr glucose intolerance Jak2 , Lep , Lepr granulosa cell tumor Lepr Growth Disorders Jak2 growth hormone insensitivity syndrome with immune dysregulation 1 Stat3 Haemophilus Infections Ptpn11 head and neck squamous cell carcinoma Irs1 , Stat3 heart disease Jak2 , Stat3 heart valve disease Jak2 Helicobacter Infections Ptpn11 , Socs3 hemorrhagic disease Ptpn11 hepatocellular adenoma Ptpn11 hepatocellular carcinoma Irs1 , Irs2 , Jak2 , Lep , Lepr , Socs3 , Stat3 hepatocellular clear cell carcinoma Lep , Lepr Hepatomegaly Lep , Lepr hereditary breast ovarian cancer syndrome Jak2 hereditary multiple exostoses Ptpn11 Hereditary Neoplastic Syndromes Jak2 , Ptpn11 heroin dependence Lep high grade glioma Ptpn11 Hodgkin's lymphoma Ptpn1 human immunodeficiency virus infectious disease Lepr , Socs3 Huntington's disease Lep Hydrops Fetalis Ptpn11 hyper IgE recurrent infection syndrome 1 Stat3 hyper IgE syndrome Stat3 Hyperalgesia Jak2 , Lepr , Stat3 Hypercapnia Lep Hypercholesterolemia Lep hyperglycemia Irs2 , Lep , Lepr hyperinsulinism Irs1 , Lep , Lepr , Ptpn1 Hyperphagia Lep , Lepr Hyperplasia Lep hypertension Lep , Lepr , Ptpn1 Hypertriglyceridemia Lep , Socs3 hypertrophic cardiomyopathy Ptpn11 hyperuricemia Jak2 , Stat3 hypogonadism Lep , Lepr Hypoventilation Lep idiopathic generalized epilepsy Socs3 idiopathic pulmonary fibrosis Stat3 idiopathic scoliosis Ptpn11 infertility Lepr Inflammation Jak2 , Lep , Ptpn1 , Stat3 inflammatory bowel disease Stat3 influenza Ptpn11 inherited metabolic disorder Lepr Insulin Resistance Irs1 , Irs2 , Lep , Lepr , Ptpn1 , Socs3 intellectual disability Lepr , Ptpn11 Intestinal Reperfusion Injury Jak2 invasive ductal carcinoma Socs3 irritant dermatitis Stat3 juvenile myelomonocytic leukemia Ptpn11 juvenile rheumatoid arthritis Stat3 kidney disease Lepr kidney failure Lepr Kidney Reperfusion Injury Lep Knee Osteoarthritis Lep , Lepr learning disability Ptpn11 Left Ventricular Hypertrophy Lepr Leptin Receptor Deficiency Lepr leukemia Jak2 , Ptpn11 limb ischemia Ptpn1 limited scleroderma Jak2 lipid metabolism disorder Lep liver cancer Jak2 liver cirrhosis Jak2 , Stat3 liver disease Socs3 Liver Injury Jak2 , Stat3 Liver Neoplasms Stat3 Liver Reperfusion Injury Jak2 long QT syndrome Ptpn11 long QT syndrome 1 Ptpn11 lung adenocarcinoma Jak2 , Ptpn11 lung carcinoma Jak2 lung disease Lep Lung Neoplasms Stat3 lung non-small cell carcinoma Jak2 , Lep , Stat3 lung squamous cell carcinoma Ptpn11 lymphangioleiomyomatosis Stat3 Lymphatic Metastasis Socs3 , Stat3 lymphoma Ptpn11 lymphoproliferative syndrome Stat3 malignant astrocytoma Ptpn11 maturity-onset diabetes of the young type 1 Irs1 , Irs2 Mediastinal Neoplasms Ptpn1 medulloblastoma Irs2 , Stat3 Memory Disorders Stat3 mesenteric vascular occlusion Jak2 metabolic dysfunction-associated steatohepatitis Jak2 , Lepr metabolic dysfunction-associated steatotic liver disease Irs1 , Irs2 , Jak2 , Lep , Lepr , Stat3 Metabolic Syndrome Irs1 , Irs2 , Lep , Lepr metachondromatosis Ptpn11 microcephaly Ptpn11 middle cerebral artery infarction Stat3 morbid obesity Lep , Lepr multiple myeloma Ptpn11 Multisystem Autoimmune Disease, Infantile-Onset, 1 Stat3 myelofibrosis Jak2 myeloid leukemia associated with Down Syndrome Ptpn11 myeloid neoplasm Jak2 myeloproliferative neoplasm Jak2 myocardial infarction Jak2 Myocardial Ischemia Jak2 , Lepr , Socs3 Myocardial Reperfusion Injury Jak2 , Lep , Lepr , Stat3 Nasal Polyps Lepr , Stat3 nasal type extranodal NK/T-cell lymphoma Stat3 nasopharynx carcinoma Jak2 , Stat3 Neoplasm Invasiveness Stat3 Neoplasm Metastasis Jak2 , Stat3 Neoplastic Cell Transformation Irs1 , Jak2 , Stat3 nephritis Lepr nephroblastoma Stat3 nephrotic syndrome Jak2 Nerve Degeneration Lep neuroblastoma Ptpn11 Neurodevelopmental Disorders Ptpn11 neurofibroma Ptpn11 neurofibromatosis-Noonan syndrome Ptpn11 neuronal ceroid lipofuscinosis Sh2b1 neutropenia Stat3 Niemann-Pick disease type C1 Jak2 , Stat3 Noonan Like Syndrome Ptpn11 Noonan syndrome Ptpn11 Noonan syndrome 1 Ptpn11 Noonan syndrome 3 Ptpn11 Noonan syndrome with multiple lentigines Ptpn11 Noonan syndrome with multiple lentigines 1 Ptpn11 Noonan Syndrome-Like Disorder with or without Juvenile Myelomonocytic Leukemia Ptpn11 obesity Irs1 , Irs2 , Jak2 , Lep , Lepr , Ptpn1 , Sh2b1 , Socs3 , Stat3 obstructive sleep apnea Lep , Lepr Ollier disease Ptpn11 Oral Ulcer Lep osteoarthritis Lep Osteochondroma Ptpn11 osteoporosis Irs1 , Irs2 , Lep , Lepr ovarian cancer Stat3 Ovarian Neoplasms Stat3 Overweight Lepr Oxygen-Induced Retinopathy Stat3 pancreas disease Lepr pancreatic cancer Stat3 pancreatitis Lepr Paraproteinemias Ptpn11 Parkinson's disease Lep patent ductus arteriosus Ptpn11 patent foramen ovale Ptpn11 periodontitis Stat3 peripartum cardiomyopathy Stat3 pituitary gland disease Lepr plasma cell neoplasm Ptpn11 pleomorphic xanthoastrocytoma Lep Pneumococcal Pneumonia Lep , Lepr polycystic ovary syndrome Lep polycythemia Jak2 polycythemia vera Jak2 Polydipsia Lep Polyuria Lep portal hypertension Jak2 pre-eclampsia Lep , Lepr pre-malignant neoplasm Irs1 , Stat3 Precocious Puberty Lepr Pregnancy Complications Jak2 primary biliary cholangitis Jak2 , Lep , Lepr primary immunodeficiency disease Lepr , Stat3 Primary Ovarian Failure Sh2b1 primary ovarian insufficiency Jak2 , Lepr , Sh2b1 proliferative diabetic retinopathy Ptpn1 prostate cancer Stat3 prostate carcinoma Stat3 Prostatic Neoplasms Irs1 , Jak2 , Lep , Stat3 proteinuria Lep , Lepr psoriasis Stat3 psoriatic arthritis Stat3 ptosis Ptpn11 pulmonary fibrosis Lepr , Stat3 pulmonary hypertension Lepr , Stat3 Pulmonary Hypertension, Hypoxia-Induced Stat3 Pyogenic Granuloma Stat3 RASopathy Ptpn11 rectum adenocarcinoma Stat3 renal cell carcinoma Lep , Stat3 renal fibrosis Lepr Reperfusion Injury Jak2 , Lep , Socs3 , Stat3 Respiratory Tract Infections Lepr Retina Reperfusion Injury Stat3 retinal detachment Jak2 Rett syndrome Ptpn1 rheumatoid arthritis Jak2 , Stat3 rhinitis Lep Right Ventricular Hypertrophy Lepr , Ptpn11 Romano-Ward Syndrome Ptpn11 schizophrenia Sh2b1 scoliosis Ptpn11 scrapie Jak2 , Stat3 Sepsis Irs1 , Jak2 , Lep , Socs3 , Stat3 Sepsis-Associated Encephalopathy Jak2 , Stat3 short bowel syndrome Lep , Lepr skin melanoma Stat3 Skin Neoplasms Stat3 sleep apnea Lepr spermatogenic failure 57 Ptpn11 Spinal Cord Injuries Jak2 , Lep Spinal Fractures Lepr Splenomegaly Jak2 Spontaneous Abortions Jak2 squamous cell carcinoma Ptpn11 , Stat3 Staphylococcal Pneumonia Ptpn11 status epilepticus Socs3 steatotic liver disease Jak2 , Lep , Lepr , Socs3 stomach cancer Jak2 , Ptpn11 , Stat3 Stomach Neoplasms Irs2 , Stat3 strabismus Ptpn11 Stroke Jak2 , Ptpn1 Subarachnoid Hemorrhage Stat3 systemic lupus erythematosus Jak2 T-cell acute lymphoblastic leukemia Ptpn11 , Stat3 T-cell non-Hodgkin lymphoma Stat3 Tachycardia Lep tetralogy of Fallot Ptpn11 Thrombocythemia 3 Jak2 thrombocytopenia Ptpn11 thrombocytosis Jak2 Thromboembolism Jak2 thrombosis Jak2 Tongue Neoplasms Stat3 transient cerebral ischemia Jak2 , Stat3 tricuspid valve insufficiency Ptpn11 type 1 diabetes mellitus Stat3 type 2 diabetes mellitus Irs1 , Irs2 , Lep , Lepr , Ptpn1 , Socs3 , Stat3 ulcerative colitis Jak2 , Stat3 urinary bladder cancer Jak2 , Stat3 Uterine Cervical Neoplasms Jak2 , Stat3 uterine fibroid Irs1 Varicose Ulcer Lepr Venous Thrombosis Jak2 Ventricular Dysfunction, Left Lepr Ventricular Premature Complexes Ptpn11 Ventricular Tachycardia Ptpn11 Weight Gain Lep , Lepr Weight Loss Lep Werner syndrome Ptpn11 Wounds and Injuries Ptpn1
