Dissecting the Shared and Context-Dependent Pathways Mediated by the p140Cap Adaptor Protein in Cancer and in Neurons

Abstract

The p140Cap adaptor protein is a scaffold molecule physiologically expressed in few epithelial tissues, such as the mammary gland, and in differentiated neurons. While the role of p140Cap in mammary gland epithelia is not still understood, we already know that a significant subset of breast cancers express p140Cap. In the subgroup of ERBB2-amplified breast cancers, a high p140Cap status predicts a significantly lower probability of developing a distant event and a clear difference in survival. p140Cap is causal in dampening ERBB2-positive tumor cell progression, impairing tumor onset and growth, and counteracting epithelial mesenchymal transition, resulting in decreased metastasis formation. Since only a few p140Cap interacting proteins have been identified in breast cancer and the molecular complexes and pathways underlying the cancer function of p140Cap are largely unknown, we generated a p140Cap interactome from ERBB2-positive breast cancer cells, identifying cancer specific components and those shared with the synaptic interactome. We identified 373 interacting proteins in cancer cells, including those with functions relevant to cell adhesion, protein homeostasis, regulation of cell cycle and apoptosis, which are frequently deregulated in cancer. Within the interactome, we identified 15 communities (clusters) with topology-functional relationships. In neurons, where p140Cap is key in regulating synaptogenesis, synaptic transmission and synaptic plasticity, it establishes an extensive interactome with proteins that cluster to sub complexes located in the postsynaptic density. p140Cap interactors converge on key synaptic processes, including synaptic transmission, actin cytoskeleton remodeling and cell-cell junction organization. Comparing the breast cancer to the synaptic interactome, we found 39 overlapping proteins, a relatively small overlap. However, cell adhesion and remodeling of actin cytoskeleton clearly emerge as common terms in the shared subset. Thus, the functional signature of the two interactomes is primarily determined by organ/tissue and functional specificity, while the overlap provides a list of shared functional terms, which might be linked to both cancer and neurological functions.

Trps1 targets Ccnd1 to regulate mouse Leydig cell proliferation

“…tested SRCIN1 enrichment against GO, KEGG, and Reactome databases. For enrichment analysis of GO Biological Process (GO‐BP) terms, the most significantly enriched terms included “apoptosis” and “cell cycle.” In the Reactome database, “regulation of apoptosis” and “ubiquitin‐dependent degradation of cyclin D1” were also found to be highly enriched 34 . The results also showed increased expression of Srcin1 , followed by decreased Ccnd1 expression in Leydig cells (Figures 2B, 2G; 3B, 3G; Figures 4B, 4G).…”

p130Cas/BCAR1 and p140Cap/SRCIN1 Adaptors: The Yin Yang in Breast Cancer?

“…Furthermore, p140Cap exerts an overall inhibitory effect on counteracting the EMT invasive program of ERBB2 tumors, as shown by a marked down-regulation of the EMT transcription factors Snail, Slug, and Zeb1 as well as by the reduction of the mesenchymal cell–cell adhesion protein N-cadherin. Noteworthy, p140Cap is also able to interact with E-Cadherin, both with classical biochemical approaches ( Damiano et al, 2010 ) or by a comprehensive analysis of the p140Cap interactome in breast cancer cells ( Chapelle et al, 2019 ). Overall, these data indicate its possible contribution in strengthening the adherence junction stability through the relocalization and immobilization of E-cadherin at the plasma membrane ( Figure 3B ).…”

“…Recently, we generated a p140Cap interactome from the ERBB2-positive breast cancer TuBo cell, a clonal line established in vitro from a BALB-NeuT mouse mammary carcinoma ( Rovero et al, 2000 ; Chapelle et al, 2019 ). The identification and functional characterization of p140Cap co-immunoprecipitated proteins, performed by Mass Spectrometry and subsequent bioinformatic analysis, revealed 374 putative interacting partners.…”

“…The identification and functional characterization of p140Cap co-immunoprecipitated proteins, performed by Mass Spectrometry and subsequent bioinformatic analysis, revealed 374 putative interacting partners. Among these proteins are present crucial components of signaling pathways that regulate specific cellular functions such as cell-substrate junction, focal adhesion organization, cell-cell adhesions, cell cycle and apoptosis, and protein homeostasis ( Chapelle et al, 2019 ).…”

The p140Cap adaptor protein as a molecular hub to block cancer aggressiveness

“…Interestingly, the p140Cap interactome in crude synaptosome revealed 351 p140Cap interactors which cluster to sub complexes mostly located in the postsynaptic density (PSD) [ 19 ]. The p140Cap interactome was also recently generated in ERBB2-positive BC cells [ 15 , 85 ], leading to the identification of 373-interacting proteins. Consistent with the previously described role for p140Cap in cell–matrix and cell–cell adhesion, and with the already known interactors, the GO Ontology has shown significant enrichment for “Cell- substrate junction” and “Focal adhesion” terms [ 11 , 14 ].…”