Tyrosine Phosphorylation Disrupts Elongin Interaction and Accelerates SOCS3 Degradation

Haan, Serge; Ferguson, Paul W.; Sommer, Ulrike; Hiremath, Meena; McVicar, Daniel W.; Heinrich, Peter C.; Johnston, James A.; Cacalano, Nicholas A.

doi:10.1074/jbc.m303170200

Cited by 98 publications

(119 citation statements)

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“…Tyrosine phosphorylation of SOCS3 on Y204 and Y221 residues blocks interaction with Elongin C and directs SOCS3 to degradation. Thus, this suggests a mechanism whereby tyrosine kinases can escape negative feedback control from SOCS3 by phosphorylation on specific tyrosine residues [96].…”

Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 95%

“…While these proteins generally controls receptor signaling by destabilizing receptor or its substrate proteins, they can also cooperate with receptors in mediating mitogenic signaling. In some cases receptors can escape negative regulation by phosphorylation on specific tyrosine residues as demonstrated in the case of SOCS3 [96].…”

Section: Socs Proteins In Rtk Regulated Diseasesmentioning

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: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 95%

Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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“…Previous reports have shown that SOCS-3 is phosphorylated on tyrosine residues in response to cytokines and growth factors. 27,28 Phosphorylation influences SOCS-3's ability to interact with the RasGAP and Elongin B/C proteins 28,29 and is thus potentially important for proper function of SOCS-3. In our control experiment, treatment of COS-1 cells transiently transfected with wt SOCS-3 with the protein-tyrosine phosphatase inhibitor sodium pervanadate indeed resulted in detection of high levels of tyrosine phosphorylated SOCS-3 ( Figure 3a).…”

Section: Socs-3 In Ctclmentioning

confidence: 99%

Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNα

Brender

Lovato

et al. 2004

Leukemia

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“…The SOCS box has been demonstrated to regulate the stability of SOCS proteins as well as SOCS-interacting molecules (4,14,15,37). SOCS1 accelerates the degradation of Jak1, Jak2, a TEL-Jak2 oncogenic fusion protein, the GEF Vav, and IRS-1 and IRS-2 (16 -20).…”

Section: Discussionmentioning

confidence: 99%

“…Plasmids, Antibodies, and Fusion Proteins-C-terminally FLAGtagged or HA-tagged wild-type and mutant SOCS3 cDNAs cloned into the mammalian expression vector pME18S and the retroviral expression vector pMX-IRES-GFP have been described previously (36,37). SOCS3 pY 204 /pY 221 peptide spanning amino acids 200 -225 (DSpYEKVTQLPGPIREFLDQpYDAPL) as well as pY 204 and pY 221 singly phosphorylated peptides and unphosphorylated controls were supplied by Research Genetics.…”

Section: Methodsmentioning

confidence: 99%

Tyrosine-phosphorylated SOCS3 Interacts with the Nck and Crk-L Adapter Proteins and Regulates Nck Activation

Sitko

Guevara

Cacalano

2004

Journal of Biological Chemistry

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Suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine and growth factor signal transduction. Although the affect of SOCS proteins on the Jak-STAT pathway has been well characterized, their role in the regulation of other signaling modules is not well understood. In the present study, we demonstrate that SOCS3 physically interacts with the SH2/SH3-containing adapter proteins Nck and Crk-L, which are known to couple activated receptors to multiple downstream signaling pathways and the actin cytoskeleton. Our data show that the SOCS3/Nck and SOCS3/Crk-L interactions depend on tyrosine phosphorylation of SOCS3 Tyr 221 within the conserved SOCS box motif and intact SH2 domains of Nck and Crk-L. Furthermore, SOCS3 Tyr 221 forms a YXXP motif, which is a consensus binding site for the Nck and Crk-L SH2 domains. Expression of SOCS3 in NIH3T3 cells induces constitutive recruitment of a Nck-GFP fusion protein to the plasma membrane and constitutive tyrosine phosphorylation of endogenous Nck. Our findings suggest that SOCS3 regulates multiple cytokine and growth factor-activated signaling pathways by acting as a recruitment factor for adapter proteins.The suppressors of cytokine signaling (SOCS) 1 represent a heterogeneous family of proteins characterized by an N-terminal protein-protein interaction domain followed by a conserved 40 amino acid motif known as the SOCS box (1-4). The N termini of SOCS proteins are divergent and can contain SH2 domains, WD40 repeats, SPRY domains, or ankyrin repeats (3, 4). The most well characterized SOCS subfamily is represented by CIS, SOCS1, SOCS2, and SOCS3, which contain a short (ϳ40 amino acids) N-terminal domain and an internal SH2 domain. These proteins have been shown to inhibit Janus kinase (Jak) signaling through SH2-dependent interactions with phosphotyrosine residues on cytokine receptors or in the catalytic loop of Jak kinases, to block downstream activation of the signal transducers and activators of transcription (STATs) (5-13).The SOCS box is also a protein-protein interaction domain and mediates binding to elongin C, a component of a multisubunit E3 ubiquitin ligase. It has been shown to regulate the stability of SOCS proteins as well as SOCS-associated signaling molecules (4, 14 -15). The current models for the mechanisms of SOCS protein function include direct inhibition of Jak-STAT signaling as well as targeting of signal transduction molecules for degradation through the ubiquitination machinery via its association with elongin C (16 -21). A well studied example of the latter mechanism is inhibition of transformation by the TEL-Jak2 oncogenic fusion protein by SOCS1. SOCS1 binds Tel-Jak2 through its SH2 domain and induces its proteasome-mediated destruction (16 -18). Other signaling proteins that are known to be degraded by SOCS include insulin receptor substrate (IRS)-1 and IRS-2, the guanine nucleotide exchange factor (GEF) Vav, and focal adhesion kinase (FAK) (19 -21).Gene-targeting studies have demonstrated the essential role of SOCS1 ...

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Tyrosine Phosphorylation Disrupts Elongin Interaction and Accelerates SOCS3 Degradation

Cited by 98 publications

References 49 publications

SOCS proteins in regulation of receptor tyrosine kinase signaling

SOCS proteins in regulation of receptor tyrosine kinase signaling

Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNα

Tyrosine-phosphorylated SOCS3 Interacts with the Nck and Crk-L Adapter Proteins and Regulates Nck Activation

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