CD295 

LEPR (leptin receptor), OBR, B219

Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Placenta
Heart
Hematopoietic Cell
Liver
Small intestine
Pancreas
Ovary
Prostate
130 / 130
150 / 150

Expression
CD295 is expressed on broad and hematopoietic cells and weak monocytes.  Expression is also in the heart, placenta, fetal liver, pancreas, small intestine, prostate and ovary.  Expression is low in lung and kidney .

Structure
MOLECULAR FAMILY NAME:  Belongs to the immunoglobulin gene family.

CD295 is a single-pass type-1 1144 aa glycoprotein.  It contains a 21 signal sequence, an 818 aa extracellular domain which contains a N-terminal fibronectin type-3 domain, an Ig-like domain, 3 FnIII domains and a WSXWS motif, a 23 aa transmembrane domain and a 303 aa intracellular cytoplasmic domain which contains a Box1 motif that is essential for JAK2/STAT3 activation.  The WSXWS motif is essential for protein folding, efficient intracellular transport and cell surface receptor binding.  CD295 belongs to cytokine receptor family within the Ig gene superfamily.  Leptin (LEP), an adipocyte-specific hormone that regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure, acts through CD295, the leptin receptor (LEPR).
 
MOLECULAR MASS

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 5 different isoforms.  The long isoform is a functional receptor for leptin and all other isoforms have short cytoplasmic domains or are secreted.

POST-TRANSLATIONAL MODIFICATION

On ligand binding, phosphorylation is on two concerved C-terminal tyrosine residues by JAK2.  Tyr-986 is required for complete binding and activation of PTPN11, ERK/FOS activation and, for interaction with SOCS3 whereas phosphorylation on Tyr-1141 is required for STAT3 binding/activation.

Ligands
LIGANDS AND MOLECULE ASSOCIATED WITH CD295

CD295 binds leptin.

Function
CD295 mediates the effects of the multi-functional hormone leptin.  CD295 signaling is a critical step in the normal physiology of many cell types regulating food intake, lipid metabolism, immune function, fertility, angiogenesis and bone formation.  Leptin induced CD295 signaling in arcuate nucleus of the hypothalamus modulates neuronal signaling in a negative feedback loop to regulate food intake and energy expenditure.  Additionally, CD295 signaling is involved in lipid handling by jejunal epithelium which when disrupted may contribute to obesity and acts as a receptor for the obestity factor.  The action of CD295 is critical for the regulation of body weight, suppressing appetite and regulating adipose tissue mass.  On ligand binding, it mediates signaling through JAK/STAT3.  It regulates fat metabolism and the immune dysfunction in obesity and, in a  hematopoietic pathway, is required for normal lymphoiesis.  It may play a role in reproduction and can mediate the ERK/FOS signaling pathway.  The cytoplasmic domain may be essential for intracellular signal transduction by activation of JAK tyrosine kinase and STATs.  More recently it has been demonstrated that CD295 has a role to play in the immune system, stimulating cytokine release, in the proliferation of anti-apoptotic T cells and influencing hematopoiesis precursors.   Naive and memory T cell proliferation is differentially regulated by leptin-mediated CD295 signaling and promotes the secretion of pro-inflammatory cytokines such as IFN and IL-2 while suppressing regulatory cytokines such as IL-4 thereby favoring a Th1 response.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD295 IN INTACT ANIMAL

Platelets express CD295 and aggregate in the presence of high concentration of leptin (within the concentration range found circulating in obese people) and ADP.  This effect was suggested as a possible link between obesity and cardiovascular disease associated with syndrome X and diabetes.  CD295 deficient mice are obese, infertile, hyperphagic, hypothermic, have increased bone formation and bone density, diabetic, have delayed wound healing and have impaired T cell responses.  ZDF rats lack functional CD295 and they display defective neo-vascularization develop diabetes characterized by reduced glucose stimulated insulin secretion increased intracellular triglyceride accumulation and upregulation of lipogenic enzymes and apoptotic pancreatic β cells.  CD295 deficient humans who are morbidly obese have significant hypothyroidism with reduced secretion of growth hormone and thyrotropin and have low cell counts and impaired cell mediated responses.  These individuals are predisposed to infectious diseases and are at greater risk of succumbing to infections in childhood.

Comments
MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD295: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD295: No information.

ADDITIONAL INSIGHTS

For further information see Bennett, B. D. et al (1996) Curr. Biol. 6: 1170-1180.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3953P48357
Antibodies

Revised June 25, 2008


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