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Insulin-induced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor in adipocytes in vitro. 2010

Takanobu Yamamoto, and Takayoshi Suganami, and Minako Kiso-Narita, and Peggy A Scherle, and Yasutomi Kamei, and Mitsuaki Isobe, and Shigeki Higashiyama, and Yoshihiro Ogawa
Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a type I transmembrane protein, which is proteolytically cleaved to release a soluble form via members of the a disintegrin and metalloproteinase (ADAM) family of proteolytic enzymes. This study was designed to elucidate the molecular mechanism underlying insulin-induced HB-EGF shedding in adipocytes in vitro. The 3T3-L1 adipocytes with stable expression of alkaline phosphatase (AP)-tagged proHB-EGF (3T3-L1/HB-EGF-AP adipocytes) were developed and AP activities of conditioned media were determined. Using 3T3-L1/HB-EGF-AP adipocytes, we demonstrated that insulin induces HB-EGF shedding in differentiated 3T3-L1 adipocytes in a dose- and time-dependent manner. There is no significant increase in insulin-induced HB-EGF shedding in undifferentiated 3T3-L1 preadipocytes. Studies with metalloprotease inhibitors suggested that insulin-induced HB-EGF shedding in adipocytes is mediated at least in part via ADAM17. Treatment with recombinant HB-EGF results in a dose- and time-dependent increase in HB-EGF shedding in adipocytes, which is significantly suppressed by pharmacologic blockade of ADAM17 (P < 0.01). Moreover, insulin-induced HB-EGF shedding in adipocytes is significantly inhibited by AG1478, an EGF receptor antagonist (P < 0.01). This study provides in vitro evidence that insulin induces HB-EGF shedding in 3T3-L1 adipocytes. Our data also suggest the role of ADAM17 in insulin-induced HB-EGF shedding in adipocytes.

UI MeSH Term Description Entries
D007328 Insulin A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1). Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D011799 Quinazolines A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D000072198 ADAM17 Protein A disintegrin and metalloproteinase domain-containing protein that cleaves the membrane-bound precursor of TUMOR NECROSIS FACTOR-ALPHA to its mature form. It cleaves several other CELL SURFACE PROTEINS, including INTERLEUKIN-1 RECEPTOR TYPE II; TRANSFORMING GROWTH FACTOR ALPHA; L-SELECTIN; MUCIN-1; and AMYLOID BETA-PROTEIN PRECURSOR. It can also function as an activator of the Notch signaling pathway by mediating the cleavage of NOTCH RECEPTORS. ADAM-17,ADAM-17 Protein,CD156b Antigen,Disintegrin and Metalloproteinase Domain-Containing Protein 17,TACA (Enzyme),TACE (Enzyme),TNF-alpha Convertase,TNF-alpha Converting Enzyme,Tumor Necrosis Factor Alpha Convertase,Tumor Necrosis Factor-alpha Convertase,Tumor Necrosis Factor-alpha Converting Enzyme,ADAM 17 Protein,Antigen, CD156b,Convertase, TNF-alpha,Disintegrin and Metalloproteinase Domain Containing Protein 17,TNF alpha Convertase,TNF alpha Converting Enzyme,Tumor Necrosis Factor alpha Converting Enzyme
D000469 Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1.
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D017667 Adipocytes Cells in the body that store FATS, usually in the form of TRIGLYCERIDES. WHITE ADIPOCYTES are the predominant type and found mostly in the abdominal cavity and subcutaneous tissue. BROWN ADIPOCYTES are thermogenic cells that can be found in newborns of some species and hibernating mammals. Fat Cells,Lipocytes,Adipocyte,Cell, Fat,Cells, Fat,Fat Cell,Lipocyte
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D051722 ADAM Proteins A family of membrane-anchored glycoproteins that contain a disintegrin and metalloprotease domain. They are responsible for the proteolytic cleavage of many transmembrane proteins and the release of their extracellular domain. A Disintegrin and Metalloprotease Protein,A Disintegrin and Metalloprotease Proteins,ADAM (A Disintegrin and Metalloprotease) Proteins

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