How the selective recruitment and stimulation of either Cdc42 or Rac is achieved is currently unknown, as both TCR- as well as Torin 1 CEACAM3-initiated signalling involve the guanine nucleotide exchange TWS119 factor Vav. Nevertheless, our findings that Nck associates with phosphorylated CEACAM3 and recruits the WAVE2 complex shed light on the downstream events following Rac GTP loading. WAVE2 is part of a pentameric complex that is intrinsically inactive. Besides WAVE2, Abi, and Brk1, the complex contains the proteins Sra and Nap1, which seem to shield the carboxy-terminal VCA domain of WAVE2, thereby preventing WAVE-initiated Arp2/3 complex stimulation and actin nucleation. Though the precise details are currently unknown, the actin nucleation promoting activity of the WAVE complex appears to depend on multiple inputs including association with GTP-loaded Rac, binding to phosphoinositides, and phosphorylation of WAVE that all seem to alter the conformation of the complex. Interestingly, one integral component of the WAVE complex, Nap1, has been initially identified as an Nck binding partner in a yeast-two-hybrid screen. Interaction between Nap1 and Nck is mediated by proline-rich sequences in Nap1 and Nck SH3 domains allowing a constitutive, phosphorylation-independent association as also detected in our analysis. Though direct binding of the SH3 domain of IRSp53, a BAR-domain containing protein localized at lamellipodial membrane protrusions, has been shown to contribute to activation of the WAVE complex, it is not known, if the SH3 domain-mediated association of Nck with Nap1 can result in an allosteric activation of the complex. However, the Nck- Nap1 interaction could clearly contribute to the subcellular localization of the WAVE complex, thereby directing the actin nucleation machinery to clustered and tyrosine phosphorylated CEACAM3. Moreover, Nck could affect WAVE complex activation indirectly. In particular, Nck is known to bind the cytoplasmic tyrosine kinase Abl, that phosphorylates WAVE2 at tyrosine residue Y150 providing an essential post-translational modification for full activation of the WAVE complex. Abl directly binds to Abi, another constituent of the WAVE complex, and additional interactions between Nck SH3 domains and Abl might facilitate or stabilize such an association. Nck also associates with the actin nucleation promoting factor N-WASP, an effector of GTP-loaded Cdc42. Nck/N-WASP driven actin polymerization is critical for pedestal formation in mammalian cells infected with enteropathogenic E. coli and for actin-based intracellular motility driven by the vaccinia virus protein A36R. Based on our data, we can not rule out an involvement of WASP family members in CEACAM3-induced lamellipodia formation.