title: c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2.
abstract: Adipocyte differentiation, or adipogenesis, is a complex and highly regulated process. A recent proteomic analysis has predicted that the nonreceptor tyrosine kinase Abelson murine leukemia viral oncogene (c-Abl) is a putative key regulator of adipogenesis, but the underlying mechanism remained obscure. We found that c-Abl was activated during the early phase of mouse 3T3-L1 preadipocyte differentiation. Moreover, c-Abl activity was essential and its inhibition blocked differentiation to mature adipocytes. c-Abl directly controlled the expression and activity of the master adipogenic regulator peroxisome proliferator-activator receptor gamma 2 (PPARγ2). PPARγ2 physically associated with c-Abl and underwent phosphorylation on two tyrosine residues within its regulatory activation function 1 (AF1) domain. We demonstrated that this process positively regulates PPARγ2 stability and adipogenesis. Remarkably, c-Abl binding to PPARγ2 required the Pro12 residue that has a phenotypically well-studied common human genetic proline 12 alanine substitution (Pro12Ala) polymorphism. Our findings establish a critical role for c-Abl in adipocyte differentiation and explain the behavior of the known Pro12Ala polymorphism.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Rom
authors.initials: R
authors.lastname: Keshet
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Zina
authors.initials: Z
authors.lastname: Bryansker Kraitshtein
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Matan
authors.initials: M
authors.lastname: Shanzer
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Adler
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nina
authors.initials: N
authors.lastname: Reuven
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel yosef.shaul@weizmann.ac.il.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shaul
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D001549:Benzamides; D047495:PPAR gamma; D010879:Piperazines; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D011392:Proline; D016315:Proto-Oncogene Proteins c-abl
keywords: PPAR gamma; Pro12Ala polymorphism; adipogenesis; c-Abl; differentiation