A key step in cell migration is the dynamic formation and disassembly of adhesions at the front and the concomitant movement and release of adhesions in the rear of the cell. Fibroblasts maintained in the absence of serum have stable adhesions within the rear of the cell and exhibit reduced trailing-edge retraction resulting in an elongated cell phenotype. Addition of lysophosphatidic acid (LPA) induced the movement of adhesions and retraction of the trailing edge, thus mimicking tail retraction in a migrating cell. Focal adhesion kinase (FAK), guanine nucleotide exchange factors (GEF) for Rho and the Rho effector Rho kinase II (ROCKII) are crucial for the regulation of adhesion movement and trailing-edge retraction. Downregulation of FAK by small interfering RNAs or small hairpin RNAs blocked LPA-induced adhesion movement and restoration of cell shape. This phenotype was rescued by the ectopic expression of PDZ-RhoGEF or a RhoA-effector-domain mutant that activates ROCK. Knockdown of PDZ-RhoGEF or ROCKII inhibited LPA-induced trailing-edge retraction and adhesion movement. Moreover, overexpressed PDZ-RhoGEF co-immunoprecipitated with FAK and localized to FAK-containing adhesions. These studies support a model in which FAK and PDZ-RhoGEF cooperate to induce Rho/ROCKII-dependent focal adhesion movement and trailing-edge retraction in response to LPA.

Signal transduction occurs by the reversible assembly of oligomeric protein complexes that include both enzymatic proteins and proteins without known enzymatic activity. These nonenzymatic components can serve as scaffolds or anchors and regulate the efficiency, specificity, and localization of the signaling pathway. Here we report the identification of MORG1 (mitogen-activated protein kinase organizer 1), a member of the WD-40 protein family that was isolated as a binding partner of the extracellular signalregulated kinase (ERK) pathway scaffold protein MP1. MORG1 specifically associates with several components of the ERK pathway, including MP1, Raf-1, MEK, and ERK, and stabilizes their assembly into an oligomeric complex. MORG1 facilitates ERK activation when cells are stimulated with lysophosphatidic acid, phorbol 12-myristate 13-acetate, or serum, but not in response to epidermal growth factor. Suppression of MORG1 by short interfering RNA leads to a marked reduction in ERK activity when cells are stimulated with serum. We propose that MORG1 is a component of a modular scaffold system that participates in the regulation of agonist-specific ERK signaling.

Apico-basal polarity is typical of cells present in differentiated epithelium while front-rear polarity develops in motile cells. In cancer development, the transition from epithelial to migratory polarity may be seen as the hallmark of cancer progression to an invasive and metastatic disease. Despite the morphological and functional dissimilarity, both epithelial and migratory polarity are controlled by a common set of polarity complexes Par, Scribble and Crumbs, phosphoinositides, and small Rho GTPases Rac, Rho and Cdc42. In epithelial tissues, their mutual interplay ensures apico-basal and planar cell polarity. Accordingly, altered functions of these polarity determinants lead to disrupted cell-cell adhesions, cytoskeleton rearrangements and overall loss of epithelial homeostasis. Polarity proteins are further engaged in diverse interactions that promote the establishment of front-rear polarity, and they help cancer cells to adopt different invasion modes. Invading cancer cells can employ either the collective, mesenchymal or amoeboid invasion modes or actively switch between them and gain intermediate phenotypes. Elucidation of the role of polarity proteins during these invasion modes and the associated transitions is a necessary step towards understanding the complex problem of metastasis. In this review we summarize the current knowledge of the role of cell polarity signaling in the plasticity of cancer cell invasiveness.

The androgen receptor (AR) remains functionally important in the development and progression of prostate cancer even when the disease seems androgen ''independent.'' Because signal transduction by growth factor receptors increases in advanced prostate cancer and is capable of sensitizing the AR to androgen, there is considerable interest in determining the mechanisms by which signaling systems can modulate AR function. We show herein that the adaptor/scaffolding protein receptor for activated C kinase 1 (RACK1), which was previously reported to interact with the AR, modulates the tyrosine phosphorylation of AR and its interaction with the Src tyrosine kinase. We also show that down-regulation of RACK1 by short interfering RNA inhibits growth and stimulates prostate-specific antigen transcription in androgentreated prostate cancer cells. Our results suggest that RACK1 mediates the cross-talk of AR with additional binding partners, such as Src, and facilitates the tyrosine phosphorylation and transcriptional activity of the AR. (Cancer Res 2006; 66(22): 11047-54)