Dissection of the insulin signaling pathway via quantitative phosphoproteomics

Marcus Krüger, Irina Kratchmarova, Blagoy Blagoev, Yu Hua Tseng, C. Ronald Kahn, Matthias Mann

Research output: Contribution to journalArticlepeer-review

217 Scopus citations


The insulin signaling pathway is of pivotal importance in metabolic diseases, such as diabetes, and in cellular processes, such as aging. Insulin activates a tyrosine phosphorylation cascade that branches to create a complex network affecting multiple biological processes. To understand the full spectrum of the tyrosine phosphorylation cascade, we have defined the tyrosine-phosphoproteome of the insulin signaling pathway, using high resolution mass spectrometry in combination with phosphotyrosine immunoprecipitation and stable isotope labeling by amino acids in cell culture (SILAC) in differentiated brown adipocytes. Of 40 identified insulin-induced effectors, 7 have not previously been described in insulin signaling, including SDR, PKCδ binding protein, LRP-6, and PISP/PDZK11, a potential calcium ATPase binding protein. A proteomic interaction screen with PISP/PDZK11 identified the calcium transporting ATPase SERCA2, supporting a connection to calcium signaling. The combination of quantitative phosphoproteomics with cell culture models provides a powerful strategy to dissect the insulin signaling pathways in intact cells.

Original languageEnglish
Pages (from-to)2451-2456
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
StatePublished - 19 Feb 2008
Externally publishedYes


  • Diabetes
  • Insulin action
  • Tyrosine phosphorylation


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