The ins and outs of syntenin, a multifunctional intracellular adaptor protein

Beekman, Jeffrey M.; Coffer, Paul J.

doi:10.1242/jcs.026401

Cited by 103 publications

(114 citation statements)

References 47 publications

(92 reference statements)

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“…MDA-9/syntenin contains a tandem repeat of PDZ domains that plays a central role in signaling pathways by organizing networks of receptors and in targeting selected cellular proteins to multiprotein complexes (2)(3)(4). MDA-9/syntenin is up-regulated in a large spectrum of human malignancies, including melanoma (4 -7).…”

mentioning

confidence: 99%

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

Aissaoui

Prévost

Boucharaba

et al. 2015

Journal of Biological Chemistry

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Background: MDA-9/syntenin and tissue factor (TF) are overexpressed in most types of human cancer. Results: Induction of MDA-9/syntenin in melanoma involves the binding of FVIIa and FX to TF on the cell surface, which initiates a signaling circuit essential for cell motility and metastasis of melanoma. Conclusion: MDA-9/syntenin is an important TF-regulated gene. Significance: Targeting TF-mediated MDA-9/syntenin may represent a novel therapeutic strategy for eliminating cancer.

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confidence: 99%

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

Aissaoui

Prévost

Boucharaba

et al. 2015

Journal of Biological Chemistry

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“…The PDZ2 domain of syntenin has been associated with various proteins 25 . Of the more than 20 syntenin-binding proteins, only syndecan-2 has been demonstrated to regulate dendritic spine formation 17,18,26 .…”

Section: Resultsmentioning

confidence: 99%

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

et al. 2015

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Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulindependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.

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“…Syntenin/MDA-9 is an adapter protein that consists of an N-terminal domain, followed by a tandem PDZ module and a small C-terminal domain (Beekman and Coffer, 2008;Sarkar et al, 2004Sarkar et al, , 2008. We have previously shown that interleukin-5 signaling activates Sox4 transcriptional activity by syntenin associating with the IL5Ra-chain, and further demonstrated syntenin to modulate interleukin-5-induced eosinophil differentiation of hematopoietic stem cells (Geijsen et al, 2001;Beekman et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

et al. 2011

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The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitinindependent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.

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The ins and outs of syntenin, a multifunctional intracellular adaptor protein

Cited by 103 publications

References 47 publications

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

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