Adenomatous Polyposis Coli and Asef Function Downstream of Hepatocyte Growth Factor and Phosphatidylinositol 3-Kinase

The Adenomatous Polyposis Coli-associated Guanine Nucleotide Exchange Factor Asef Is Involved in Angiogenesis

“…Our findings that Asef is required for bFGF-and VEGF-mediated angiogenesis raise the possibility that Asef and APC function downstream of growth factors acting through receptor tyrosine kinases. In line with this notion, we have recently found that Asef functions downstream of EGF and hepatocyte growth factor in epithelial cells (19,28). In this study, we showed that bFGF and VEGF induce the accumulation and colocalization of Asef and APC in membrane ruffles and lamellipodia and increase the amounts of the Asef-APC complex.…”

“…These findings have encouraged us to examine the possibility that Asef could function as a downstream component of signal transduction pathways linking growth factors to morphological changes and cell migration. Indeed, we have recently found that Asef and APC function downstream of hepatocyte growth factor and that Asef is required for hepatocyte growth factor-induced cell migration (19). In the present study, we examined whether Asef functions downstream of bFGF and VEGF, which play critical roles in angiogenesis, a process important for embryonic development and pathogenesis including tumorigenesis (20).…”

Hepatocyte Growth Factor-induced Asef-IQGAP1 Complex Controls Cytoskeletal Remodeling and Endothelial Barrier

“…Asef also does not become properly activated, which impairs its regulation of local Rac signaling and peripheral actin remodeling. Asef activity in the IQGAP1 complex may be also stimulated by IQGAP1-assisted translocation to the cell membrane, where Asef may interact via its pleckstrin homology domain with PIP 3 , the phosphoinositide product of PI 3-kinase (51). Interaction with PIP 3 is necessary to activate the catalytic activity of the DH domains of some GEFs (16).…”

Structural basis for the recognition of Asef by adenomatous polyposis coli

“…Asef is constitutively activated by truncated APC, stimulates the GEF activity of Cdc42, and promotes tumor invasion and angiogenesis [17,[20][21][22][25][26][27]. It has been noted that compounds targeting Asef could be novel anti-tumor reagents [26,27].…”

“…The activated Asef catalyzes the exchange of GDP for GTP in Cdc42, decreases cell-cell adhesion, and promotes cell migration [17,[20][21][22]. In colorectal cancers, truncated APC constitutively activates Asef and Cdc42, which upregulate the expression of matrix metalloproteinase 9 (MMP9) via the c-Jun N-terminal kinase (JNK) pathway, thus promotes cancercell migration and angiogenesis [25][26][27].…”