Suppressor of Cytokine Signaling 6 (SOCS6) Negatively Regulates Flt3 Signal Transduction through Direct Binding to Phosphorylated Tyrosines 591 and 919 of Flt3

Kazi, Julhash U.; Sun, Jianmin; Phung, Bengt; Zadjali, Fahad; Flores‐Morales, Amilcar

doi:10.1074/jbc.m112.376111

Cited by 68 publications

(82 citation statements)

References 29 publications

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“…Association of SOCS6 with KIT and FLT3 apparently plays a role in control of receptor downstream signaling. SOCS6 selectively blocks ERK1/2 and p38 phosphorylation but not phosphorylation of AKT or STAT5β [17,18]. Thus SOCS6 does not solely regulate KIT or FLT3 signaling by destabilizing receptor.…”

Section: Socs6mentioning

confidence: 92%

“…SOCS6 has also been found to associate with ligand-stimulated FLT3 as well as with oncogenic FLT3. This interaction increases FLT3 ubiquitination and degradation [17]. Association of SOCS6 with KIT and FLT3 apparently plays a role in control of receptor downstream signaling.…”

Section: Socs6mentioning

confidence: 97%

“…Cells expressing these receptor induce SOCS6 mRNA expression in response to their respective ligands [17,18] suggesting that KIT and FLT3 regulate SOCS6 expression. It has been shown that PMA, a potent activator of PKC, can stabilize SOCS6 proteins through activation of ERK1/2 [68].…”

Section: Socs6mentioning

confidence: 99%

“…SOCS6 has also been shown to be tyrosine phosphorylated in response to the SCF and FLstimulation [17,18]. However, so far no report has identified the phospho-tyrosine residues in SOCS6.…”

Section: Socs6mentioning

confidence: 99%

“…The KIR motif can inhibit kinase activity by impairing access to substrates, while the SH2 domain can competitively inhibit the binding of other proteins to phosphotyrosine residues. The interactions between RTKs and SOCS have been shown to be selective, occurring only with the ligand-stimulated wild-type receptors or with constitutively active mutant receptors [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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SOCS proteins in regulation of receptor tyrosine kinase signaling.Uddin, Kazi; Kabir, Nuzhat N; Flores-Morales, Amilcar; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., Kabir, N. N., Flores-Morales, A., & Rönnstrand, L. (2014). SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and Molecular Life Sciences, 71(17), 3297-3310. DOI: 10.1007/s00018-014-1619-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many of this family of kinases are overexpressed or mutated in human malignancies and thus became 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 suppressor of cytokine signaling (SOCS) family proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and 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 sometimes can 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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Section: Socs6mentioning

confidence: 92%

Section: Socs6mentioning

confidence: 97%

Section: Socs6mentioning

confidence: 99%

“…SOCS6 has also been shown to be tyrosine phosphorylated in response to the SCF and FLstimulation [17,18]. However, so far no report has identified the phospho-tyrosine residues in SOCS6.…”

Section: Socs6mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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FMS-Like Tyrosine Kinase-3

Kazi

Moharram

Rönnstrand

2016

Encyclopedia of Signaling Molecules

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CD135; FLK2; FLK-2; STK1 Historical Background Receptor tyrosine kinases are cell surface receptors that transduce signals mainly from extracellular stimuli leading to activation of numerous intracellular signaling cascades. The human genome encodes 58 receptor tyrosine kinases which can be subdivided into 20 different families (Lemmon and Schlessinger 2010). Within the 20 different families, the type III receptor tyrosine kinase family, also known as PDGFR family, consists of five receptor tyrosine kinases including PDGFRA, PDGFRB, KIT, CSF1R, and FLT3. The Fms-like tyrosine kinase 3 (FLT3) is a receptor for the dimeric FLT3 ligand (FL). The receptor was first described by two different groups in human and mouse (Matthews et al. 1991; Rosnet and Marchetto. 1991; Rosnet et al. 1991). In human, it was mapped to chromosome 13q12 and in mouse it was mapped to chromosome 5.

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