S100P is a novel interaction partner and regulator of IQGAP1

Annika Heil, Ali Reza Nazmi, Max Koltzscher, Michaela Poeter, Judith Austermann, Nicole Assard, Jacques Baudier, Kozo Kaibuchi, Volker Gerke

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36 Citations (Scopus)

Abstract

Ca2+-binding proteins of the S100 family participate in intracellular Ca2+ signaling by binding to and regulating specific cellular targets in their Ca2+-loaded conformation. Because the information on specific cellular targets of different S100 proteins is still limited, we developed an affinity approach that selects for protein targets only binding to the physiologically active dimer of an S100 protein. Using this approach, we here identify IQGAP1 as a novel and dimer-specific target of S100P, a member of the S100 family enriched in the cortical cytoskeleton. The interaction between S100P and IQGAP1 is strictly Ca2+-dependent and characterized by a dissociation constant of 0.2 μM. Binding occurs primarily through the IQ domain of IQGAP1 and the first EF hand loop of S100P, thus representing a novel structural principle of S100-target protein interactions. Upon cell stimulation, S100P and IQGAP1 co-localize at or in close proximity to the plasma membrane, and complex formation can be linked to altered signal transduction properties of IQGAP1. Specifically, the EGF-induced tyrosine phosphorylation of IQGAP1 that is thought to function in assembling signaling intermediates at IQGAP1 scaffolds in the subplasmalemmal region is markedly reduced in cells overexpressing S100P but not in cells expressing an S100P mutant deficient in IQGAP1 binding. Furthermore, B-Raf binding to IQGAP1 and MEK1/2 activation occurring downstream of IQGAP1 in EGF-triggered signaling cascades are compromised at elevated S100P levels. Thus, S100P is a novel Ca2+-dependent regulator of IQGAP1 that can down-regulate the function of IQGAP1 as a signaling intermediate by direct interaction.

Original languageEnglish
Pages (from-to)7227-7238
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number9
DOIs
Publication statusPublished - 04-03-2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Heil, A., Nazmi, A. R., Koltzscher, M., Poeter, M., Austermann, J., Assard, N., Baudier, J., Kaibuchi, K., & Gerke, V. (2011). S100P is a novel interaction partner and regulator of IQGAP1. Journal of Biological Chemistry, 286(9), 7227-7238. https://doi.org/10.1074/jbc.M110.135095