Genomic amplicons target vesicle recycling in breast cancer

Abstract

Aberrant endocytosis, vesicle targeting, and receptor recycling represent emerging hallmarks of cancer. In this issue of the JCI, Zhang and colleagues demonstrate that RAB-coupling protein (RCP; also known as RAB11FIP1) is a "driver" of the 8p11-12 amplicon in human breast cancer and mouse xenograft models of mammary carcinogenesis (see the related article beginning on page 2171). Their finding that RAB GTPase function enables genomic amplification to confer aggressiveness to mammary tumors adds significantly to the body of evidence supporting pivotal roles for receptor trafficking in the proliferation and metastasis of cancer.

Figure 1. Role of RCP in integrin and RTK trafficking during tumor cell migration.

(A) Activated RCP associates with β₁ integrin and acts to link this integrin with RTKs at recycling endosomes. The consequence of RCP-dependent corecycling of integrin and RTK is enhanced signaling, which drives cell proliferation and cell migration in 2D and 3D matrices. (B) RCP recruits a spatially restricted cycling population of receptors to the tips of invasive pseudopods during tumor cell migration in 3D microenvironments.

Figure 2. RCP protein-protein interaction network.

RAB11FIP family members function by binding to multiple different RAB proteins to coordinate vesicle function and polarity. In order to effectively target the functions of RCP, it will be necessary to understand how the interaction of RCP with its partners regulates cellular functions. Using Interologous Interaction Database v1.71 (http://ophid.utoronto.ca/i2d), we constructed a protein-protein interaction network highlighting RCP interactions with other RAB and VPS (vacuolar protein sorting) family members. The network comprises 159 proteins and 447 physical protein interactions. Only direct, physical interactions were included, covering human-curated, high-throughput, and interologous interactions (individual interaction sources are listed at http://ophid.utoronto.ca/ophidv2.201/statistics.jsp). Protein function according to Gene Ontology (http://www.geneontology.org/), vesicle function, and polarity are highlighted according to the legends. Red-highlighted nodes represent direct physical interactions with RCP. RAB protein family members are shown as rectangles; blue edges correspond to direct interactions among RAB proteins. VPS protein family members are indicated by hexagons; green edges correspond to direct interactions among VPS proteins. PRK family proteins are triangle nodes; purple edges show direct interactions among PRK proteins. Black edges identify interactions that connect RAB, VPS, and PRK family proteins. Network visualization was done in NAViGaTOR, version 2.1.15 (http://ophid.utoronto.ca/navigator).