To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression with the development of a fibroblastic morphology characteristic of metastatic cells. Adhesion receptors of the cadherin family have been implicated in development and maintenance of the differentiated epithelial phenotype. Cadherin mediated cell adhesion requires the activity of the cytosolic proteins of the Rho subfamily Rho, Rac and Cdc42.Rac is a small GTPase that is activated by GEF, in particular ARHGEF6. Rac mediates key cellular processes in response to upstream regulators such as growth factors, integrins and hyaluronic acid binding receptor CD44. Rac is a key downstream target of PI3K. Rac is also activated by integrin via FAK. Interaction between CD44 and TIAM1 can also activate Rac. TIAM1 is a known GDP/GTP exchange factor for Rac. TIAM1 and the cytoskeletal protein Ankyrin physically associate as a complex. Ankyrin binding to TIAM1 activates Rac. Upon activation, Rac interacts with and regulates a spectrum of functionally diverse downstream effectors, initiating a network of cytoplasmic and nuclear signaling cascades.
A number of proteins act as targets for Rac including PAKs, IQGAP1, CDC42, POR1 and POSH. Rac binds p67(Phox) to increase activation of the NADPH oxidase system and production of reactive oxygen species (ROS), which mediates activation of NF-κB-dependent gene expression. Rac binds the WAVE complex to release active WAVE which promotes actin polymerization in lamellipodia through activation of the ARP2/3 complex. Rac also binds to the actin binding protein IQGAP which is implicated in regulation of cell-cell adhesion and microtubule orientation. Recently, a novel Rac interacting protein, POR1, has been identified that plays a role in membrane ruffling. p140SRA1 is another novel target for Rac that is involved in membrane ruffling.
Rac is also implicated in the regulation of PLD which is critical in cell growth. Rac binds to and activates PIP5K, which increases the amount of PIP2. Rac coordinately activates p70S6K and JNK via MLK3 activation. Once activated, JNK enters the nucleus and phosphorylates transcription factors such as c-Jun, c-Fos, Elk1 and Elk4. Rac also activates DBS, which further activates RhoA and Cdc42. In neurons, Rac acts through CDK5 and p35 to phosphorylate and downregulate PAK1, increasing neuronal migration. PAK1 also phosphorylates and activates LIMK, which phosphorylates and inhibits cofilin. Cofilin stimulates actin depolymerization and changes in cell structure.
Rac controls the generation of ROS, both in leukocytes and non-hematopoietic cells, and is necessary for cadherin-dependent adhesion. Rac activation is required for the fully transformed phenotype induced by oncogenes such as TIAM1 and Ras. In addition, Rac activation perturbs cadherin contacts with a concomitant change in cell shape including formation of lamellae and conversion to a fibroblastic morphology.