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

Abstract

The p140Cap adaptor protein is a scaffold molecule encoded by the SRCIN1 gene, which is physiologically expressed in several epithelial tissues and in the neurons. However, p140Cap is also strongly expressed in a significant subset of cancers including breast cancer and neuroblastoma. Notably, cancer patients with high p140Cap expression in their primary tumors have a lower probability of developing a distant event and ERBB2-positive breast cancer sufferers show better survival. In neuroblastoma patients, SRCIN1 mRNA levels represent an independent risk factor, which is inversely correlated to disease aggressiveness. Consistent with clinical data, SRCIN1 gain or loss of function mouse models demonstrated that p140Cap may affect tumor growth and metastasis formation by controlling the signaling pathways involved in tumorigenesis and metastatic features. This study reviews data showing the relevance of SRCIN1/p140Cap in cancer patients, the impact of SRCIN1 status on p140Cap expression, the specific mechanisms through which p140Cap can limit cancer progression, the molecular functions regulated by p140Cap, along with the p140Cap interactome, to unveil its key role for patient stratification in clinics.

Keywords: Chromosome 17q12; Gene amplification; Interactome analysis; Metastasis; SRCIN1; miRNA.

Fig. 1

p140Cap and intrinsic disorder. Disorder probability of p140Cap human amino acid sequence (sequence ID: NP_079524.2), with DisEMBL computational tool. Figure downloaded from: DisEMBL https://dis.embl.de/, sequence ID: NP_079524, Intrinsic Protein Disorder Prediction 1.52). Predictions are shown according to each of the three different criteria to define the disorder level of protein residues, namely: loops or coils (blue line): loop assignment can be used as a necessary but not sufficient requirement for a disorder; -hot loops (red lines): constitute a subset of loops having a high degree of mobility as determined by C-alpha temperature (B-) factors. It follows that highly dynamic loops should be considered a protein disorder; missing coordinates in X-ray structure as defined by REMARK465 entries in PDB (green lines). Non-assigned electron densities in X-ray 3D structures most often reflect intrinsic disorder, and can be used in disorder predictions. For more detail, see [24]. The predicted probabilities are shown as curves along the sequences; scores should be compared to the corresponding random expectation value (dotted lines)

Fig. 2

p140Cap structure and main interactors. p140Cap consists of an N-terminal tyrosine-rich region (Tyr-rich), an actin-binding domain (ABD), a proline rich domain (Pro1), a coil-coiled region (C1-C2), two domains rich in charged amino acids (CH1, CH2) and a C-terminal proline-rich domain (Pro2). Lipidation (Myristoylation, Myr) and functional tyrosine phosphorylation (PY) EPLYA and EGLYA are show. The binding regions of Csk, β-Catenin, Vinexin, EB3, Cortactin, p130Cas and Src are shown by the red lines

Fig. 3

Alteration frequencies of SRCIN1 gene in cancer. Frequencies of SRCIN1 gene alterations in various types of cancer included in the TCGA PanCancer Atlas Studies. Mutations, deep deletions, amplifications and multiple alterations are shown in different colors. Figure download from: cBioPortal for Cancer Genomics (https://www.cbioportal.org/)

Fig. 4

p140Cap expression in cancer patients correlates with good prognosis. a Kaplan–Meier curves for DRFI (left panel), and DRBC (right panel) stratified by p140Cap IHC expression in a cohort of 92 ERBB2-positive patients [15]. b Kaplan–Meier curves for overall (left panel) and event-free (right panel) survival stratified by SRCIN1 expression in a cohort of 498 NB patients [47]

Fig. 5

Impact of SRCIN1/p140Cap gene alteration in ERBB2/HER2-amplified breast cancer and neuroblastoma. Amplification of the SRCIN1 gene in ERBB2/HER-2-positive breast cancer patients impairs tumor growth and metastasis mainly through the down-regulation of Tiam1/Rac1 axis. SRCIN1 aberrant alterations such as translocations, deletions or loss of heterozygosity promote tumor growth, metastasis and drug resistance in NB patients, consistent with the loss of p140Cap expression, and inhibition of both Src and STAT3/Jak2 pathways