The many faces of the SOCS box

Piessevaux, Julie; Lavens, Delphine; Peelman, Frank; Tavernier, Jan

doi:10.1016/j.cytogfr.2008.08.006

Cited by 152 publications

(151 citation statements)

References 124 publications

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“…Thus the eya-Socs synergy observed in our screen could reflect interactions relevant to those other pathways. Mechanistically, although SOCS proteins belong to the family of Cullin-Ring E3 ubiquitin ligases (reviewed in Piessevaux et al 2008), a model in which they target Eya for degradation seemed unlikely because the predicted increase in Eya levels upon Socs knockdown should enhance, rather than suppress, GMR . Eya WT phenotypes.…”

Section: Resultsmentioning

confidence: 99%

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

2016

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The transcriptional coactivator and phosphatase eyes absent (Eya) is dynamically compartmentalized between the nucleus and cytoplasm. Although the nuclear transcriptional circuits within which Eya operates have been extensively characterized, understanding of its cytoplasmic functions and interactions remains limited. Our previous work showed that phosphorylation of Drosophila Eya by the Abelson tyrosine kinase can recruit Eya to the cytoplasm and that eya-abelson interactions are required for photoreceptor axons to project to correct layers in the brain. Based on these observations, we postulated that photoreceptor axon targeting might provide a suitable context for identifying the cytoplasmic signaling cascades with which Eya interacts. Using a dosesensitive eya misexpression background, we performed an RNA interference-based genetic screen to identify suppressors. Included among the top 10 hits were nonreceptor tyrosine kinases and multiple members of the Jak/Stat signaling network (hop, Stat92E, Socs36E, and Socs44A), a pathway not previously implicated in axon targeting. Individual loss-of-function phenotypes combined with analysis of axonal projections in Stat92E null clones confirmed the importance of photoreceptor autonomous Jak/Stat signaling. Experiments in cultured cells detected cytoplasmic complexes between Eya and Hop, Socs36E and Socs44A; the latter interaction required both the Src homology 2 motif in Socs44A and tyrosine phosphorylated Eya, suggesting direct binding and validating the premise of the screen. Taken together, our data provide new insight into the cytoplasmic phosphotyrosine signaling networks that operate during photoreceptor axon guidance and suggest specific points of interaction with Eya.KEYWORDS SH2; genetic screen; retinal determination network; eye development; Socs44A A remarkable feature of multicellular animal development is that the complexity and diversity in tissue type and patterning is achieved using fewer than a dozen signaling pathways, including Notch, receptor tyrosine kinase, Wnt, Hedgehog, TGFb, Jak/Stat, and Hippo. These cascades are repeatedly deployed in different contexts to regulate the majority of the critical proliferation, survival, specification, and differentiation decisions (reviewed in Voas and Rebay 2004;Housden and Perrimon 2014). One strategy to achieve context-specific developmental regulation is for proteins and pathways to function together in interconnected networks. Further, individual proteins within these networks may encode multiple independent functions that can be executed in distinct parts of the cell, cell types, or stages of development. In this way, even a modest number of individual proteins and core pathways can create vast combinatorial possibilities.Eyes absent (Eya), a protein conserved from plants to humans, presents an ideal model to study integration because its multifunctionality and dynamic subcellular localization provide opportunities for interaction with many signaling pathways (reviewed in Jemc andRebay 2007 an...

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Section: Resultsmentioning

confidence: 99%

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

2016

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“…Rab40b belongs to a sub-family of Rab40 GTPases that includes two other closely related members, Rab40a and Rab40c, and is characterized by the presence of a SOCS box at their C-terminal half (Fig. 3A) (Piessevaux et al, 2008;Stein et al, 2012). Interestingly, depletion of Rab40a did not have any effect on MMP2-Myc or MMP9-Myc secretion.…”

Section: Rab40b Gtpase Is Required For Mmp2 and Mmp9 Secretionmentioning

confidence: 99%

Rab40b regulates MMP2 and MMP9 trafficking during invadopodia formation and breast cancer cell invasion

Jacob

Jing

Lee³

et al. 2013

Journal of Cell Science

124

136

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SummaryInvadopodia-dependent degradation of the basement membrane plays a major role during metastasis of breast cancer cells. Basement membrane degradation is mediated by targeted secretion of various matrix metalloproteinases (MMPs). Specifically, MMP2 and MMP9 (MMP2/9) possess the ability to hydrolyze components of the basement membrane and regulate various aspects of tumor growth and metastasis. However, the membrane transport machinery that mediates targeting of MMP2/9 to the invadopodia during cancer cell invasion remains to be defined. Because Rab GTPases are key regulators of membrane transport, we screened a human Rab siRNA library and identified Rab40b GTPase as a protein required for secretion of MMP2/9. We also have shown that Rab40b functions during at least two distinct steps of MMP2/9 transport. Here, we demonstrate that Rab40b is required for MMP2/9 sorting into VAMP4-containing secretory vesicles. We also show that Rab40b regulates transport of MMP2/9 secretory vesicles during invadopodia formation and is required for invadopodia-dependent extracellular matrix degradation. Finally, we demonstrate that Rab40b is also required for breast cancer cell invasion in vitro. On the basis of these findings, we propose that Rab40b mediates trafficking of MMP2/9 during invadopodia formation and metastasis of breast cancer cells.

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“…Based on forced expression, a regulatory potential for SOCS2 has been suggested in several pathways; however, the physiological relevance of these results is controversial. Because SOCS2 lacks a KIR domain, the inhibitory function of SOCS2 is dependent on competitive binding via its SH2 domain and, even more important, on the proteasomal degradation of the proteins with which it interacts (8). Apart from altered GH signaling, SOCS2-deficient mice have also been shown to exhibit alterations in their immune system.…”

Section: Endritic Cells (Dcs) Play Important Roles In Immune Recognmentioning

confidence: 99%

“…Second, the shared KIR motif of SOCS1 and SOCS3 directly inhibits JAK activity, apparently by acting as a pseudosubstrate for the kinase (7). Third, SOCS proteins exert their inhibitory action, at least in part, by enhancing ubiquitination and subsequent proteasomal depletion of receptors or signal-transducing molecules (8). The degradation of interacting proteins is attributed to the SOCS-box, which interacts with and stabilizes complexes of ubiquitin ligases (9).…”

Section: Endritic Cells (Dcs) Play Important Roles In Immune Recognmentioning

confidence: 99%

Suppressor of Cytokine Signaling 2 Is a Feedback Inhibitor of TLR-Induced Activation in Human Monocyte-Derived Dendritic Cells

Posselt

Schwarz

Duschl

et al. 2011

The Journal of Immunology

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Dendritic cells (DCs) are key players in initiating and directing the immune response. Therefore, their activation state and functional differentiation need to be tightly controlled. The activating stimuli and their signaling networks have long been an area of focus in DC research. Recent investigations have also shed light on the mechanisms of counterregulation and fine-tuning of DC functions. One class of proteins involved in these processes is the family of suppressors of cytokine signaling (SOCS), whose members were originally described as feedback inhibitors of cytokine-induced JAK/STAT signaling. Essential roles in DC function have been assigned to SOCS1 and SOCS3. In this article, we show that SOCS2 also is involved in DC regulation. In human and in murine DCs, SOCS2 is a highly TLR-responsive gene, which is expressed in a time-delayed fashion beginning 8 h after TLR ligation. Functionally, silencing of SOCS2 in DCs results in hyperphosphorylation of STAT3 at later time points. As a consequence, SOCS2-deficient DCs secrete increased amounts of the cytokines IL-1β and IL-10, both being transcriptional targets of STAT3. We propose a model in which SOCS2 acts as a negative regulator of TLR-induced DC activation. The delayed expression of SOCS2 provides a mechanism of late-phase counterregulation and limitation of inflammation-driving DC activity.

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The many faces of the SOCS box

Cited by 152 publications

References 124 publications

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

Rab40b regulates MMP2 and MMP9 trafficking during invadopodia formation and breast cancer cell invasion

Suppressor of Cytokine Signaling 2 Is a Feedback Inhibitor of TLR-Induced Activation in Human Monocyte-Derived Dendritic Cells

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