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 wellstudied 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.

c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice

“…A proteomic analysis revealed that c-Abl was a potential key regulator of adipogenesis via regulation of the expression and activity of peroxisome proliferator-activator receptor γ 2 (PPARγ2), the master adipogenic regulator controlling adipogenesis [23,24]. These findings indicate that c-Abl participates in adipocytes metabolism regulation in vitro.…”

Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation

“…c-Abl is a non-receptor tyrosine kinase protein that regulates cellular proliferation and cytoskeletal remodeling (40). c-Abl is also involved in the differentiation of diverse cell types, including adipocytes, osteoblasts, and dendritic cells (41)(42)(43). The results of our study suggest that c-Abl tyrosine kinase signaling may play an important role in the differentiation of CD14 + monocytes into fibrocytes.…”

Investigations on Binding Pattern of Kinase Inhibitors with PPARγ: Molecular Docking, Molecular Dynamic Simulations, and Free Energy Calculation Studies

“…The associations of PPAR γ with signaling molecules including receptor and nonreceptor kinases corroborate the cross-talk function between the two signaling proteins [11, 24, 25, 30, 31]. Kumar et al (2005) identified L-tyrosine derivatives as potential PPAR α / γ inhibitors [32, 33].…”