p140Cap Regulates GABAergic Synaptogenesis and Development of Hippocampal Inhibitory Circuits

Russo, Isabella; Gavello, Daniela; Menna, Elisabetta; Vandael, David; Veglia, Carola; Morello, Noemi; Corradini, Irene; Focchi, Elisa; Alfieri, Annalisa; Angelini, Costanza; Bianchi, F.; Morellato, Alessandro; Marcantoni, Andrea; Sassoè‐Pognetto, Marco; Ottaviani, Matteo Maria; Yekhlef, Latefa; Giustetto, Maurizio; Taverna, Stefano; Carabelli, Valentina; Matteoli, Michela; Carbone, Emilio; Turco, Emilia; Defilippi, Paola

doi:10.1093/cercor/bhx306

Cited by 18 publications

(15 citation statements)

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“…p140Cap in differentiated neurons controls synaptic plasticity [19,20], and regulates GABAergic synaptogenesis and development of hippocampal inhibitory circuits [21]. Taking into account the functional role of p140Cap in differentiated neural cells, we set out to tackle its relevance in human NB, analyzing the expression of the p140Cap encoding gene SRCIN1, its genomic profile and its causal role in NB aggressiveness.…”

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confidence: 99%

The SRCIN1/p140Cap adaptor protein negatively regulates the aggressiveness of neuroblastoma

et al. 2019

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Neuroblastoma is the most common extra-cranial pediatric solid tumor, responsible for 13-15% of pediatric cancer death. Its intrinsic heterogeneity makes it difficult to target for successful therapy. The adaptor protein p140Cap/SRCIN1 negatively regulates tumor cell features and limits breast cancer progression. This study wish to assess if p140Cap is a key biological determinant of neuroblastoma outcome. RNAseq profiles of a large cohort of neuroblastoma patients show that SRCIN1 mRNA levels are an independent risk factor inversely correlated to disease aggressiveness. In highrisk patients, CGH+SNP microarray analysis of primary neuroblastoma identifies SRCIN1 as frequently altered by hemizygous deletion, copy-neutral loss of heterozygosity, or disruption. Functional experiments show that p140Cap negatively regulates Src and STAT3 signaling, affects anchorage-independent growth and migration, in vivo tumor growth and spontaneous lung metastasis formation. p140Cap also increases sensitivity of neuroblastoma cells to doxorubicin and etoposide treatment, as well as to a combined treatment with chemotherapy drugs and Src inhibitors. Our functional findings point to a causal role of p140Cap in curbing the aggressiveness of neuroblastoma, due to its ability to impinge on specific molecular pathways, and to sensitize cells to therapeutic treatment. This study provides the first evidence that the SRCIN1/p140Cap adaptor protein is a key player in neuroblastoma as a new independent prognostic marker for patient outcome and treatment. Altogether, these data highlight the potential clinical impact of SRCIN1/p140Cap expression in neuroblastoma tumors, in terms of reducing cytotoxic effects of chemotherapy, one of the main issues for pediatric tumor treatment. Background Neuroblastoma (NB) is a complex disease with different outcome, responsible for a large proportion of cancer death in childhood [1, 2]. Primary NB originate from genetic abnormalities in neural crest-derived sympathoadrenal cells [1]. The International Neuroblastoma Staging System (INSS) defines 5 stages of NB progression [3], from Stages 1 and 2 (localized tumor, without lymph nodes involvement) to Stage 3 and Stage 4 (metastatic disease, with dissemination in distant organs). Stage 4S specifies a metastatic disease in children under the age of 1 year, which may undergo spontaneous regression usually associated with 90% survival rate at 5 years. The therapeutic intervention in NB (surgery for stages 1 and 2, and multipleagent chemotherapy [4, 5]), does not increase substantially

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confidence: 99%

The SRCIN1/p140Cap adaptor protein negatively regulates the aggressiveness of neuroblastoma

et al. 2019

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“…Using the CRISPR-Cas9 system combined with IUE to inactivate grid1 (Figures 1J and 1K), ppp1r12a , and arhgef12 (Figure 6F), we found that neither grid1/arhgef12 double KO nor grid1/ppp1r12a double KO further reduced the density of inhibitory synapses compared to single grid1 KO (104% ± 3% of Grid1-KO for Grid1-KO + Ppp1r12a-KO and 105% ± 4% of Grid1-KO for Grid1-KO + Arhgef12-KO; Figure 6G), indicating that GluD1 requires ARHGEF12 and PPP1R12A to operate at inhibitory synapses. Interestingly, other major partners of GluD1 (Figure 6B), such as the Rho GTPase-activating protein 32 (ARHGAP32/PX-RICS) (Nakamura et al., 2016, Uezu et al., 2016), SRCIN1 (p140cap) (Alfieri et al., 2017, Russo et al., 2019), and Ankyrin 3 (Ankyrin G) (Nelson et al., 2018), have been shown to interact with gephyrin and/or regulate inhibitory synaptogenesis. This supports the notion that GluD1 serves as a signaling hub for the formation and specification of inhibitory synapses (Figure 6H), and that the regulation of inhibitory synaptogenesis is a major function of GluD1 in the neocortex.…”

Section: Resultsmentioning

confidence: 99%

“…ARHGAP32 interacts with gephyrin, and its inactivation impairs GABA A R trafficking at synapses (Nakamura et al., 2016, Uezu et al., 2016). SRCIN1, SRGAP3, and SRGAP2 also associate with gephyrin and regulate GABAergic synaptogenesis (Alfieri et al., 2017, Fossati et al., 2016, Okada et al., 2011, Russo et al., 2019). Therefore, GluD1 trans-synaptic signaling provides local regulation of protein phosphorylation and GTPase activity and allows the recruitment of synaptic molecules for the assembly of inhibitory postsynaptic machineries in an input-specific and agonist-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons

Fossati

Assendorp

Gemin

et al. 2019

Neuron

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“…The physiologic role of p140Cap has been mainly investigated in the brain [35], where it is expressed in neurons both in the presynapse [10,36] and in the postsynapse [10,[37][38][39][40][41]. In differentiated neurons, it controls synaptic plasticity [33,40], and regulates GABAergic synaptogenesis and development of hippocampal inhibitory circuits [36]. In particular, p140Cap enters and accumulates in the dendritic spine (DS) through EB3 binding [33].…”

Section: The P140cap Adaptor Proteinmentioning

confidence: 99%

The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression: A New Paradigm in Neuroblastoma

Centonze¹,

Chapelle²,

Angelini³

et al. 2021

Pheochromocytoma, Paraganglioma and Neuroblastoma

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Neuroblastoma, the most common extra-cranial pediatric solid tumor, is responsible for 9–15% of all pediatric cancer deaths. Its intrinsic heterogeneity makes it difficult to successfully treat, resulting in overall survival of 50% for half of the patients. Here we analyze the role in neuroblastoma of the adaptor protein p140Cap, encoded by the SRCIN1 gene. RNA-Seq profiles of a large cohort of neuroblastoma patients show that SRCIN1 mRNA levels are an independent risk factor inversely correlated to disease aggressiveness. In high-risk patients, SRCIN1 was frequently altered by hemizygous deletion, copy-neutral loss of heterozygosity, or disruption. Functional assays demonstrated that p140Cap is causal in dampening both Src and Jak2 kinase activation and STAT3 phosphorylation. Moreover, p140Cap expression decreases in vitro migration and anchorage-independent cell growth, and impairs in vivo tumor progression, in terms of tumor volume and number of spontaneous lung metastasis. p140Cap also contributes to an increased sensitivity of neuroblastoma cells to chemotherapy drugs and to the combined usage of doxorubicin and etoposide with Src inhibitors. Overall, we provide the first evidence that SRCIN1/p140Cap is a new independent prognostic marker for patient outcome and treatment, with a causal role in curbing the aggressiveness of neuroblastoma. We highlight the potential clinical impact of SRCIN1/p140Cap expression in neuroblastoma tumors, in terms of reducing cytotoxic effects of chemotherapy, one of the main issues for pediatric tumor treatment.

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p140Cap Regulates GABAergic Synaptogenesis and Development of Hippocampal Inhibitory Circuits

Cited by 18 publications

References 67 publications

The SRCIN1/p140Cap adaptor protein negatively regulates the aggressiveness of neuroblastoma

The SRCIN1/p140Cap adaptor protein negatively regulates the aggressiveness of neuroblastoma

Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons

The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression: A New Paradigm in Neuroblastoma

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