Rabbit Anti-Human DOCK1 (internal) Polyclonal antibody

Cell-cell contact formation is a dynamic process requiring the coordination of cadherin-based cell-cell adhesion and integrin-based cell migration. A genome-wide RNA interference screen for proteins required specifically for cadherin-dependent cell-cell adhesion identified an Elmo-Dock complex. This was unexpected as Elmo-Dock complexes act downstream of integrin signaling as Rac guanine-nucleotide exchange factors. In this paper, we show that Elmo2 recruits Dock1 to initial cell-cell contacts in Madin-Darby canine kidney cells. At cell-cell contacts, both Elmo2 and Dock1 are essential for the rapid recruitment and spreading of E-cadherin, actin reorganization, localized Rac and Rho GTPase activities, and the development of strong cell-cell adhesion. Upon completion of cell-cell adhesion, Elmo2 and Dock1 no longer localize to cell-cell contacts and are not required subsequently for the maintenance of cell-cell adhesion. These studies show that Elmo-Dock complexes are involved in both integrin-and cadherin-based adhesions, which may help to coordinate the transition of cells from migration to strong cell-cell adhesion.

Progression of solid tumors to the metastatic stage is accountable for the majority of cancer-related deaths. Further understanding of the molecular mechanisms governing metastasis is essential for the development of antimetastatic regimens. Here, we aimed to identify Rac activators that could promote metastasis downstream of human epithelial growth factor receptor 2 (HER2). We investigated if Dedicator of Cytokinesis 1 (DOCK1), based on its evolutionarily conserved role in receptor tyrosine kinases (RTKs)-mediated Rac activation and cell invasion, could be a regulator of metastasis. We report that high expression of DOCK1 in HER2(+) and basal breast cancer subtypes inversely correlates with human patients' survival. Mechanistically, DOCK1 interacts with HER2 and promotes HER2-induced Rac activation and cell migration. To gain further insight, we developed a HER2 breast cancer mouse model with mammary-gland-specific inactivation of DOCK1. In this in vivo model, a significant decrease in tumor growth and metastasis in lungs was found in animals where DOCK1 is inactivated. Furthermore, we found that DOCK1 is required for maximal activation of two HER2 effectors, c-JUN and STAT3. Using an unbiased gene profiling approach, we identified a mammary tumor DOCK1-associated gene signature enriched for genes implicated in response to IFN type I. This analysis revealed a unique set of genes, including Receptor Transporter Protein 4 (RTP4) and STAT1, for which the expression levels can be used to independently predict breast cancer outcome in HER2(+) patients. Our work demonstrates DOCK1-Rac signaling as an HER2 effector pathway essential for HER2-mediated breast cancer progression to metastasis and offers a therapeutic opportunity to limit the spread of metastatic breast cancers.