IQGAP1 and NWASP promote human cancer cell dissemination and metastasis by regulating β1-integrin via FAK and MRTF/SRF.

Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic outgrowth. Breast and prostate cancers are common malignancies in women and men, respectively. Here, we observe that β1-integrin is required for human prostate and breast cancer cell adhesion to ECs under shear-stress conditions in vitro and to lung blood vessel ECs in vivo.

TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion.

ERBB2 overexpression in human breast cancer leads to invasive carcinoma but the mechanism is not clearly understood. Here we report that TOM1L1 is co-amplified with ERBB2 and defines a subgroup of HER2(+)/ER(+) tumours with early metastatic relapse. TOM1L1 encodes a GAT domain-containing trafficking protein and is a SRC substrate that negatively regulates tyrosine kinase signalling.

RhoC and ROCKs regulate cancer cell interactions with endothelial cells.

RhoC is a member of the Rho GTPase family that is implicated in cancer progression by stimulating cancer cell invasiveness. Here we report that RhoC regulates the interaction of cancer cells with vascular endothelial cells (ECs), a crucial step in the metastatic process. RhoC depletion by RNAi reduces PC3 prostate cancer cell adhesion to ECs, intercalation between ECs as well as transendothelial migration in vitro.

The Rho GTPase RhoB regulates cadherin expression and epithelial cell-cell interaction.

Background: The Rho GTPase RhoB has been proposed to be a tumor suppressor in cancer and is downregulated in various tumors including prostate. RhoB has different effects on cell migration depending on the cell type and conditions, but the molecular basis for this variability is unclear. RhoB regulates trafficking of membrane receptors and integrins.

Crossing the endothelial barrier during metastasis.

During metastasis, cancer cells disseminate to other parts of the body by entering the bloodstream in a process that is called intravasation. They then extravasate at metastatic sites by attaching to endothelial cells that line blood vessels and crossing the vessel walls of tissues or organs. This Review describes how cancer cells cross the endothelial barrier during extravasation and how different receptors, signalling pathways and circulating cells such as leukocytes and platelets contribute to this process.

Nectin-3 (CD113) interacts with Nectin-2 (CD112) to promote lymphocyte transendothelial migration.

Lymphocyte trafficking and migration through vascular endothelial cells (ECs) in secondary lymphoid tissues is critical for immune protection. In the present study, we investigate the role of nectin cell adhesion molecules for the migration of lymphocytes through ECs. Nectins are key players for the establishment of homotypic and heterotypic cell to cell contacts; they are required for cell to cell adherens junction formation and take part in the transendothelial migration of monocytes during the step of diapedesis, when monocytes migrate through EC junctions.

14-3-3 proteins interact with a hybrid prenyl-phosphorylation motif to inhibit G proteins.

Signaling through G proteins normally involves conformational switching between GTP- and GDP-bound states. Several Rho GTPases are also regulated by RhoGDI binding and sequestering in the cytosol. Rnd proteins are atypical constitutively GTP-bound Rho proteins, whose regulation remains elusive.

Cdc42 promotes transendothelial migration of cancer cells through β1 integrin.

Cancer cells interact with endothelial cells during the process of metastatic spreading. Here, we use a small interfering RNA screen targeting Rho GTPases in cancer cells to identify Cdc42 as a critical regulator of cancer cell-endothelial cell interactions and transendothelial migration. We find that Cdc42 regulates β1 integrin expression at the transcriptional level via the transcription factor serum response factor (SRF).

RhoB regulates cell migration through altered focal adhesion dynamics.

The Rho GTPase RhoB has been shown to affect cell migration, but how it does this is not clear. Here we show that cells depleted of RhoB by RNAi are rounded and have defects in Rac-mediated spreading and lamellipodium extension, although they have active membrane ruffling around the periphery. Depletion of the exchange factor GEF-H1 induces a similar phenotype.

Rho GTPases and cancer cell transendothelial migration.

Small Rho GTPases are major regulators of actin cytoskeleton dynamics and influence cell shape and migration. The expression of several Rho GTPases is often up-regulated in tumors and this frequently correlates with a poor prognosis for patients. Migration of cancer cells through endothelial cells that line the blood vessels, called transendothelial migration or extravasation, is a critical step during the metastasis process.

[Nectin and nectin-like molecules as markers, actors and targets in cancer].

Nectin and nectin-like (necl) proteins form a family of 9 adhesion molecules that belong to the immunoglobulin superfamily. They play a key role in different biological processes such as cell polarity, proliferation, differentiation and migration in epithelial, endothelial, immune and nervous systems. Besides their role in physiology, they have been involved in different pathological processes in humans.

Nectin-4 is a new histological and serological tumor associated marker for breast cancer.

Introduction: Breast cancer is a complex and heterogeneous disease at the molecular level. Evolution is difficult to predict according to classical histoclinical prognostic factors. Different studies highlight the importance of large-scale molecular expression analyses to improve taxonomy of breast cancer and prognostic classification.

PICK-1: a scaffold protein that interacts with Nectins and JAMs at cell junctions.

Nectin adhesion molecules are involved in the early steps of cell junction formation. Later during the polarisation process, Nectins are components of epithelial adherens junctions where they are indirectly associated with the E-cadherin/Catenins complex via the adaptator AF-6. To have a better understanding of Nectin-based cell junctions, we looked for some new Nectins' partners.

Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17.

Serum markers are extensively used in diagnostic and follow-up of cancer patients. We recently described Nectin-4, a 66-kDa adhesion molecule of the Nectin family, which is a valuable new histological and serological marker for breast carcinoma. In vivo, Nectin-4 is re-expressed in breast carcinoma, and a circulating form of Nectin-4 is detected in the sera of patients with metastatic breast cancer.

PVR (CD155) and Nectin-2 (CD112) as ligands of the human DNAM-1 (CD226) activating receptor: involvement in tumor cell lysis.

The capability of NK lymphocytes to kill tumor cells depends on different receptors/ligands interactions. In order to identify the cellular ligands recognized by "orphan" triggering receptors, mice were immunized with NK susceptible target cells. mAbs were selected that inhibited NK cytotoxicity and recognized two different molecules of 70 and 60-65 kDa.

DNAM-1 and PVR regulate monocyte migration through endothelial junctions.

DNAX accessory molecule 1 (DNAM-1; CD226) is a transmembrane glycoprotein involved in T cell and natural killer (NK) cell cytotoxicity. We demonstrated recently that DNAM-1 triggers NK cell-mediated killing of tumor cells upon engagement by its two ligands, poliovirus receptor (PVR; CD155) and Nectin-2 (CD112). In the present paper, we show that PVR and Nectin-2 are expressed at cell junctions on primary vascular endothelial cells.

Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule.

Human natural killer (NK) cells express a series of activating receptors and coreceptors that are involved in recognition and killing of target cells. In this study, in an attempt to identify the cellular ligands for such triggering surface molecules, mice were immunized with NK-susceptible target cells. On the basis of a functional screening, four mAbs were selected that induced a partial down-regulation of the NK-mediated cytotoxicity against the immunizing target cells.

Prominent role of the Ig-like V domain in trans-interactions of nectins. Nectin3 and nectin 4 bind to the predicted C-C'-C"-D beta-strands of the nectin1 V domain.

Nectins form a family of integral molecules that belong to the immunoglobulin superfamily. Their ectodomain is made of three Ig-like domains (V, C, C). This family comprises at least five members, namely nectin1, -2, -3, -4, and poliovirus receptor (PVR), that are involved in different physiological and pathological processes.