Regulation of adipogenic differentiation by LAR tyrosine phosphatase in human mesenchymal stem cells and 3T3-L1 preadipocytes.
Mesenchymal stem cells (MSCs) are multipotent adult stem cells that can differentiate into a variety of mesodermal-lineage cells. MSCs have significant potential in tissue engineering and therapeutic applications; however, the low differentiation and proliferation efficiencies of these cells in the laboratory are fundamental obstacles to their therapeutic use, mainly owing to the lack of information on the detailed signal-transduction mechanisms of differentiation into distinct lineages. With the aid of protein-tyrosine-phosphatase profiling studies, we show that the expression of leukocyte common antigen related (LAR) tyrosine phosphatase is significantly decreased during the early adipogenic stages of MSCs. Knockdown of endogenous LAR induced a dramatic increase in adipogenic differentiation, whereas its overexpression led to decreased adipogenic differentiation in both 3T3-L1 preadipocytes and MSCs. LAR reduces tyrosine phosphorylation of the insulin receptor, in turn leading to decreased phosphorylation of the adaptor protein IRS-1 and its downstream molecule Akt (also known as PKB). We propose that LAR functions as a negative regulator of adipogenesis. Furthermore, our data support the possibility that LAR controls the balance between osteoblast and adipocyte differentiation. Overall, our findings contribute to the clarification of the mechanisms underlying LAR activity in the differentiation of MSCs and suggest that LAR is a candidate target protein for the control of stem-cell differentiation.
Kim
Won-Kon
WK
Medical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Jung
Hyeyun
H
Kim
Do-Hyung
DH
Kim
Eun-Young
EY
Chung
Jin-Woong
JW
Cho
Yee-Sook
YS
Park
Sung-Goo
SG
Park
Byoung-Chul
BC
Ko
Yong
Y
Bae
Kwang-Hee
KH
Lee
Sang-Chul
SC
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000502:physiology*; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D015536:Down-Regulation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; C516772:PTPRF protein, human; C000709129:Ptprf protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2