Disease relevance of Wasf2

• Membrane ruffling, cell motility, invasion into the extracellular matrix, and pulmonary metastasis of B16F10 cells were suppressed by WAVE2 RNAi [1].
• We show that WAVEs, especially WAVE2, are essential for invasion and metastasis of melanoma cells [1].
• The Wiskott-Aldrich syndrome related protein WAVE2 is implicated in the regulation of actin-cytoskeletal reorganization downstream of the small Rho GTPase, Rac [2].
• To shed independent light on IRSp53 function we determined the localisations and dynamics of IRSp53 and WAVE2 in B16 melanoma cells [3].
• Mouse leukemia L1210 cells were exposed to continuous wave 2 MHz, 10 W/cm(2) ultrasound for 10 minutes while suspended in nitrogen mustard solution in vitro [4].

High impact information on Wasf2

• PtdIns(3,4,5)P3 binding is necessary for WAVE2-induced formation of lamellipodia [5].
• Production of PtdIns(3,4,5)P(3) at the cell membrane by myristoylated phosphatidylinositol-3-OH kinase (PI(3)K) is sufficient to recruit WAVE2 in the presence of dominant-negative Rac and latrunculin, demonstrating that PtdIns(3,4,5)P(3) alone is able to recruit WAVE2 [5].
• WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility [2].
• Moreover, exogenous expression of wild-type N-WASP or WAVE2 promoted lamellipodial formation and migration [6].
• N-WASP and WAVE2 acting downstream of phosphatidylinositol 3-kinase are required for myogenic cell migration induced by hepatocyte growth factor [6].

Biological context of Wasf2

• During our analysis of the human gene map, we also noted that WAVE2 maps to Chr region lp35-36, which frequently undergoes loss of heterozygosity and deletion in advanced stage neuroblastoma [7].
• The effect of WAVE2 silencing by RNA interference (RNAi) on the highly invasive nature of B16F10 cells was more dramatic than that of WAVE1 RNAi [1].
• Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells [1].
• In this report, we demonstrate that WAVE2 overexpression induces serum response element (SRE) activation through serum response factor [8].

Anatomical context of Wasf2

• Protein kinase A-dependent increase in WAVE2 expression induced by the focal adhesion protein vinexin [9].
• In this migration, WAVE1-deficient MEFs still could form lamellipodia but WAVE2-deficient MEFs could not [10].
• We found that WAVE2 was the predominant isoform to be expressed in primary macrophages and in cells derived from the murine monocyte/macrophage RAW264.7 cell line (RAW/LR5) [11].
• WAVE2 is essential for formation of lamellipodial structures at the cell periphery stimulated by growth factors, but it is thought that WAVE1 is dispensable for such processes in mouse embryonic fibroblasts (MEFs) [12].
• Thus, at the tip of the lamellipodial protrusion, WAVE2 generates the membrane protrusive structures containing actin filaments, and modification by WAVE1 stabilizes these structures through cell-substrate adhesion [12].

Associations of Wasf2 with chemical compounds

• Vinexin beta interacts with the proline-rich region of WAVE2 through the first and second SH3 domains of vinexin beta [9].
• WAVE2-induced SRE activation was blocked by exposure of cells to Latrunculin A, or overexpression of actin mutant R62D [8].
• WAVE2(-/-) MKs exhibited a defect in peripheral lamellipodia on fibrinogen even with phorbol 12-myristate 13-acetate (PMA) costimulation, indicating a requirement of WAVE2 for integrin alpha(IIb)beta(3)-mediated full spreading [13].

Physical interactions of Wasf2

• WAVE2 was found in a protein complex together with Abelson kinase interactor 1 (Abi1) in resting or stimulated cells [11].
• IRSp53 was found to be present in an immunoprecipitable complex with WAVE2 and Abi1 in a Rac1-activation-dependent manner in RAW/LR5 cells in vivo [14].

Regulatory relationships of Wasf2

• These results suggest that vinexin beta regulates the proteasome-dependent degradation of WAVE2 in a PKA-dependent manner [9].
• CSF-1 treatment of macrophages resulted in WAVE2 accumulation in F-actin-rich protrusions induced by CSF-1 [11].
• Wave2 activates serum response element via its VCA region and functions downstream of Rac [8].

Other interactions of Wasf2

• Mutations disrupting the interaction impaired the ability of vinexin beta to increase the amount of WAVE2 protein [9].
• Rah-promoted macropinosome formation was retarded by dominant-negative mutants of Rac1 and WAVE2, which are essential for membrane ruffling [15].
• Altogether these data identify a WAVE2-Abi1 complex crucial for the normal actin cytoskeleton reorganization and migration of macrophages in response to CSF-1 [11].
• A WAVE2-Abi1 complex mediates CSF-1-induced F-actin-rich membrane protrusions and migration in macrophages [11].
• WAVE2 overexpression did not activate NF-kappaB [8].

References