A Functional Role for the P62-ERK1 Axis in the Control of Energy Homeostasis and Adipogenesis

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2010 Feb 16

PMID 20154642

Citations 56

Authors

Sang Jun Lee

Paul T Pfluger

Ji Young Kim

Ruben Nogueiras

Angeles Duran

Gilles Pages

Jacques Pouyssegur

Matthias H Tschop

Maria T Diaz-Meco

Jorge Moscat

Affiliations

Soon will be listed here.

Abstract

In vivo genetic inactivation of the signalling adapter p62 leads to mature-onset obesity and insulin resistance, which correlate with reduced energy expenditure (EE) and increased adipogenesis, without alterations in feeding or locomotor functions. Enhanced extracellular signal-regulated kinase (ERK) activity in adipose tissue from p62-knockout (p62(-/-)) mice, and differentiating fibroblasts, suggested an important role for this kinase in the metabolic alterations of p62(-/-) mice. Here, we show that genetic inactivation of ERK1 in p62(-/-) mice reverses their increased adiposity and adipogenesis, lower EE and insulin resistance. These results establish genetically that p62 is a crucial regulator of ERK1 in metabolism.

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References

Kim K, Kim J, Wang Y, Sul H . Pref-1 (preadipocyte factor 1) activates the MEK/extracellular signal-regulated kinase pathway to inhibit adipocyte differentiation. Mol Cell Biol. 2007; 27(6):2294-308. PMC: 1820487. DOI: 10.1128/MCB.02207-06. View

Kortum R, Costanzo D, Haferbier J, Schreiner S, Razidlo G, Wu M . The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis. Mol Cell Biol. 2005; 25(17):7592-604. PMC: 1190290. DOI: 10.1128/MCB.25.17.7592-7604.2005. View

Duran A, Linares J, Galvez A, Wikenheiser K, Flores J, Diaz-Meco M . The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 2008; 13(4):343-54. DOI: 10.1016/j.ccr.2008.02.001. View

Moscat J, Diaz-Meco M . p62 at the crossroads of autophagy, apoptosis, and cancer. Cell. 2009; 137(6):1001-4. PMC: 3971861. DOI: 10.1016/j.cell.2009.05.023. View

Moscat J, Diaz-Meco M, Wooten M . Signal integration and diversification through the p62 scaffold protein. Trends Biochem Sci. 2006; 32(2):95-100. DOI: 10.1016/j.tibs.2006.12.002. View

Hu E, Kim J, Sarraf P, Spiegelman B . Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 1996; 274(5295):2100-3. DOI: 10.1126/science.274.5295.2100. View

Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M . The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes. 2005; 54(2):402-11. DOI: 10.2337/diabetes.54.2.402. View

Duran A, Serrano M, Leitges M, Flores J, Picard S, Brown J . The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell. 2004; 6(2):303-9. DOI: 10.1016/s1534-5807(03)00403-9. View

Rodriguez A, Duran A, Selloum M, Champy M, Diez-Guerra F, Maria Flores J . Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62. Cell Metab. 2006; 3(3):211-22. DOI: 10.1016/j.cmet.2006.01.011. View

10.

Laurin N, Brown J, Morissette J, Raymond V . Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002; 70(6):1582-8. PMC: 379146. DOI: 10.1086/340731. View

11.

Sale E, Atkinson P, Sale G . Requirement of MAP kinase for differentiation of fibroblasts to adipocytes, for insulin activation of p90 S6 kinase and for insulin or serum stimulation of DNA synthesis. EMBO J. 1995; 14(4):674-84. PMC: 398131. DOI: 10.1002/j.1460-2075.1995.tb07046.x. View

12.

Moscat J, Diaz-Meco M, Albert A, Campuzano S . Cell signaling and function organized by PB1 domain interactions. Mol Cell. 2006; 23(5):631-40. DOI: 10.1016/j.molcel.2006.08.002. View