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 Rac1 Pathway

Rac1 is a member of a RhoGTPase subfamily (Rac1-Rac4) that transduces extracellular signals from G-coupled protein receptors (GPCR), integrins and growth factor receptors to effector molecules that modulate multiple signaling pathways. While Rac1 supports the activation of MAPkinase pathways and gene activation, it’s most important functions include the regulation of cytoskeletal structures. Together with Rho (regulator of stress fibers) and Cdc42 (regulator of filopodia), Rac modulates the formation of focal adhesion (FA) complexes; membrane ruffles and lamellipodia that contribute to important cell functions related to cell attachment and movement.

Cell movement is a fundamental element of many biological and pathological processes including phagocytosis, wound repair, embryogenesis, inflammatory and immunological responses and tumor metastasis. A critical step in all cell movement is the extension of protrusions in the direction of the desired move. Cells accomplish this by membrane ruffling and the formation of lamellipodia. Rac1 is the primary Rho-GTPase responsible for regulating the cytoskeletal remodeling involved with lamellipodia dynamics.

Activation of these pathways requires the release of Rac1 from Rac1:RhoGDIs complexes in the cytoplasm by Rac1-GDI kinases and targeting to cell membranes by isoprenyl moieties. Membrane associated Rac1 is activated by an extensive array of tissue and location specific guanine nucleotide exchange factors (GEF) such as: Vav-GEFs (Vav1, Vav2 and p95Vav); Swap-70 (and homologue IBP); Kalirin-7 and 8; P-Rex2 and P-Rex2b; betaPIX; Duo, Trio; Fir; FERM; Ras-GRF1; GEFT and Tiam1 which exchanges GTP for Rac1 bound GDP. Some of these GEF are not direct Rac1-GTP exchangers but exchange GTP with other GTPases upstream of Rac1-GTPase activation. Activated Rac1 activates the effectors: PAK-1, -2, -3, -4, MLK3, MRCK, IQGAP, WAVE/IRSp53, FHOS (formin/diaphanous-related protein), PI 5-kinase, BLNK (B cell LiNKer protein) depending upon cell phenotype and context. GEFs provide linkage to specific receptors and downstream effectors of Rac1 signaling pathways. The activity of Rac1 is down-regulated by Rac1-GAPs (GTPase activating proteins).