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SOCS proteins in regulation of receptor tyrosine kinase signaling

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Abstract

Receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many in this family of kinases are overexpressed or mutated in human malignancies and thus became an attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressors of cytokine signaling (SOCS) family proteins are well-known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1–7, and cytokine-inducible SH2-containing protein (CIS). A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS-encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion, SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs can sometimes bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus, apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.

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Acknowledgments

This research was funded by the Swedish Cancer Society (LR), the Swedish Childhood Cancer Foundation (LR), the Swedish Research Council (LR), ALF governmental clinical grant (LR), Stiftelsen Olle Engkvist Byggmästare (JUK), the Royal Physiographic Society in Lund (JUK), Ollie och Elof Ericssons Stiftelse (JUK) and The Lars Hierta Memorial Foundation (JUK).

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Division of Translational Cancer Research, Lund University, Medicon Village, Lund, Sweden

    Julhash U. Kazi & Lars Rönnstrand

  2. Lund Stem Cell Center, Lund University, Lund, Sweden

    Julhash U. Kazi & Lars Rönnstrand

  3. Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh

    Julhash U. Kazi & Nuzhat N. Kabir

  4. Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Amilcar Flores-Morales

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  1. Julhash U. Kazi
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  2. Nuzhat N. Kabir
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  3. Amilcar Flores-Morales
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  4. Lars Rönnstrand
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Correspondence to Lars Rönnstrand.

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Kazi, J.U., Kabir, N.N., Flores-Morales, A. et al. SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell. Mol. Life Sci. 71, 3297–3310 (2014). https://doi.org/10.1007/s00018-014-1619-y

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  • DOI: https://doi.org/10.1007/s00018-014-1619-y

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