Regulation of ZAP-70 Activation and TCR Signaling by Two Related Proteins, Sts-1 and Sts-2

Carpino, Nick; Turner, Stephen J.; Mekala, Divya; Takahashi, Yutaka; Zang, Heesuk; Geiger, Terrence L.; Doherty, Peter C.; Ihle, James N.

doi:10.1016/s1074-7613(03)00351-0

Cited by 149 publications

(296 citation statements)

References 34 publications

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“…1A). STS-1 is involved in regulating signal transduction and the pathogenesis of many diseases [28,29]. Nevertheless, the role of STS-1 in SLE pathogenesis has not yet been described.…”

Section: Sts-1 Is Overexpressed In B Cells From Sle Patients and Mrl/mentioning

confidence: 99%

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

et al. 2015

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Systemic lupus erythematosus (SLE) is Keywords: Autophagy B cells Interferon-α STS-1 Systemic lupus erythematosusAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacroautophagy, conventionally referred to as autophagy, is a highly conserved lysosome-mediated catabolic process in which cytoplasmic contents are degraded and recycled [1]. Recently, various autophagic functions have been recognized in innate and adaptive immunity, including pathogen clearance, inflammasome regulation, and maintenance of tolerance [2,3]. The observations Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn of the autophagic functions that trigger or exacerbate autoimmunity show that autophagy participates in the pathogenesis of autoimmune disorders, such as systemic lupus erythematosus (SLE) [4][5][6].SLE is a potentially fatal autoimmune disease that is characterized by B-cell hyperactivation and production of autoantibodies that mainly target nuclear components [7]. Of note, B cells play a central role in the pathogenesis of SLE through the production of pathogenic autoantibodies [8,9]. Enhanced autophagic activities have been observed in B cells from SLE patients and NZB/W F1 mice [5]. Studies have increasingly demonstrated that autophagy C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2378 Guanjun Dong et al. Eur. J. Immunol. 2015. 45: 2377-2388 is involved in B-cell development, homeostasis, activation, and antibody response [10,11]. Because B cells are a major player in SLE, autophagy-mediated modulation of B cells can directly influence the pathophysiology of SLE. In fact, the contribution of autophagy to the pathogenesis of SLE has been supported by the beneficial effects of autophagy modulating molecules on disease development in SLE patients and lupus-prone mice, such as rapamycin and P140 peptide [12,13]. Given that the autophagy pathway can be considered as an effective therapeutic target in the treatment of SLE, the exploration of the enhanced autophagic activity mechanism of B cells during SLE is urgently needed. Autophagy can be provoked by host-derived cytokines, IFN-I/II or pattern recognition receptors in many cell types [2,14,15]. However, to date, the enhanced autophagic activity mechanism in SLE B cells remains unknown, although BCR ligands have been shown to induce autophagy in B cells [16,17]. Of note, IFN-α, a central cytokine in the pathogenesis of SLE, can induce and accelerate SLE symptoms in patients and mice [18]. Importantly, B cells display a significant IFN-I inducible gene signature in SLE patients [19] and IFN-α impacts B-cell functions through a variety of mechanisms, such as TLR7 expression, differentiation, and class-switch recombination [20][21][22]. Importantly, IFN-α provokes autophagy in many different cell types and JAK1-STAT1 signaling plays an absolutely necessary role in this process [23]. However, it remains unknown whether IFN-α can induce autophagy in primary human and murine B cells.ST...

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“…1A). STS-1 is involved in regulating signal transduction and the pathogenesis of many diseases [28,29]. Nevertheless, the role of STS-1 in SLE pathogenesis has not yet been described.…”

Section: Sts-1 Is Overexpressed In B Cells From Sle Patients and Mrl/mentioning

confidence: 99%

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

et al. 2015

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“…The phosphatase domain of TULA-2 appears to be tyrosinespecific, exhibiting high catalytic activity toward para-nitrophenyl phosphate, phosphotyrosyl (Tyr(P)) peptides, and Tyr(P) proteins such as protein-tyrosine kinases ZAP70, Syk, and certain members of the Src family but has no detectable activity against phosphoseryl or phosphothreonyl substrates (6,7). TULA-1 has also been reported to have protein-tyrosine phosphatase (PTP) 3 activity, although its activity is orders of magnitude lower than that of TULA-2 (6, 7). The TULA family of phosphatases is distinct from the classical PTPs, which utilize a conserved cysteine residue to catalyze the dephosphorylation reaction (8).…”

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confidence: 99%

“…TULA-1 and TULA-2 have been shown to play a role in regulating receptor-mediated signaling in T cells (3,6) as well as other signaling pathways (4,5,11,12). Interestingly, despite their similarity in protein sequence and structure, TULA-1 and TULA-2 have very different cellular functions.…”

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confidence: 99%

Determination of the Substrate Specificity of Protein-tyrosine Phosphatase TULA-2 and Identification of Syk as a TULA-2 Substrate

Chen

Ren

Kim

et al. 2010

Journal of Biological Chemistry

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TULA-1 (UBASH3A/STS-2) and TULA-2 (p70/STS-1) represent a novel class of protein-tyrosine phosphatases. Previous studies suggest that TULA-2 is sequence-selective toward phosphotyrosyl (Tyr(P)) peptides. In this work the substrate specificity of TULA-1 and -2 was systematically evaluated by screening a combinatorial Tyr(P) peptide library. Although TULA-1 showed no detectable activity toward any of the Tyr(P) peptides in the library, TULA-2 recognizes two distinct classes of Tyr(P) substrates. On the N-terminal side of Tyr(P), the class I substrates contain a proline at the Tyr(P)؊1 position, a hydrophilic residue at the Tyr(P)؊2 position, and aromatic hydrophobic residues at positions Tyr(P)؊3 and beyond. The class II substrates typically contain two or more acidic residues, especially at Tyr(P)؊1 to Tyr(P)؊3 positions, and aromatic hydrophobic residues at other positions. At the C-terminal side of Tyr(P), TULA-2 generally prefers acidic and aromatic residues. The library screening results were confirmed by kinetic analysis of representative peptides selected from the library as well as Tyr(P) peptides derived from various Tyr(P) proteins. TULA-2 is highly active toward peptides corresponding to the Tyr(P)-323 and Tyr(P)-352 sites of Syk, and the Tyr(P)-397 site of focal adhesion kinase and has lower activity toward other Tyr(P) sites in these proteins. In glycoprotein VI-stimulated platelets, knock-out of the TULA-2 gene significantly increased the phosphorylation level of Syk at Tyr-323 and Tyr-352 sites and to a lesser degree at the Tyr-525/526 sites. These results suggest that Syk is a bona fide TULA-2 substrate in platelets.

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“…Regulation of Cbl directly affects downregulation of RTKs and thereby influences cellular homeostasis. Most recently, Sprouty2 (Hall et al, 2003;Rubin et al, 2003), Sts-1/Sts-2 (Carpino et al, 2004;Feshchenko et al, 2004;Kowanetz et al, 2004) as well as bPix (Wu et al, 2003) have been described as negative regulators of Cbl. In either case, molecules act via distinct mechanisms to inhibit Cbl-mediated downregulation of RTKs, eventually resulting in sustained receptor signaling and alterations in cell responses including cell differentiation or transformation.…”

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confidence: 99%

Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix

et al. 2006

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The Pix/Cool proteins are involved in the regulation of cell morphology by binding to small Rho GTPases and kinases of the Pak family. Recently, it has been shown that bPix/Cool-1 associates with the ubiquitin ligase Cbl, which appears to be a critical step in Cdc42-mediated inhibition of epidermal-growth-factor-receptor (EGFR) ubiquitylation and downregulation. Here we show that the SH3 domain of bPix specifically interacts with a prolinearginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase. Owing to targeting of the same sequence, Cbl and Pak1 compete for binding to bPix. In this complex, Cbl mediates ubiquitylation and subsequent degradation of bPix. Our findings reveal a double feedback loop in which the Cdc42/bPix complex blocks Cbl's ability to downregulate EGFR, while Cbl in turn promotes degradation of bPix in order to escape this inhibition. Such a relationship provides a mechanism to fine-tune the kinetics of RTK endocytosis and degradation depending on the pool of active Cdc42 and the duration of EGFR signaling.

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Regulation of ZAP-70 Activation and TCR Signaling by Two Related Proteins, Sts-1 and Sts-2

Cited by 149 publications

References 34 publications

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

Determination of the Substrate Specificity of Protein-tyrosine Phosphatase TULA-2 and Identification of Syk as a TULA-2 Substrate

Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix

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