c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2.

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.
Mesh Terms:
3T3-L1 Cells, Adipocytes, Adipogenesis, Animals, Benzamides, HEK293 Cells, Humans, Mice, Mutation, Missense, NIH 3T3 Cells, PPAR gamma, Phosphorylation, Phosphotyrosine, Piperazines, Point Mutation, Polymorphism, Single Nucleotide, Proline, Protein Binding, Protein Interaction Mapping, Protein Isoforms, Protein Kinase Inhibitors, Protein Processing, Post-Translational, Protein Stability, Protein Structure, Tertiary, Proto-Oncogene Proteins c-abl, Pyrimidines, Sequence Homology, Amino Acid, Species Specificity, Transcription, Genetic
Proc. Natl. Acad. Sci. U.S.A.
Date: Nov. 18, 2014
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