Involvement of a novel ADP-ribosylation factor GTPase-activating protein, SMAP, in membrane trafficking: implications in cancer cell biology

Abstract

The endocytosis of cell membrane proteins is initiated by the binding of activated Arf6, a member of Ras-related GTPases, to the PM. A GAP specific for Arf6 triggers the budding of endocytotic vesicles from the PM by inactivating GTP-bound Arf6. We recently identified the SMAP gene that encodes an ArfGAP and is involved in the endocytosis of TfnR and possibly E-cadherin. In this review, we summarize the process of intracellular membrane trafficking, highlighting the roles played by the SMAP gene. Progression of cancer to malignancy occurs in parallel with the disappearance of E-cadherin, a central component of the adherens junction in epithelial cells. Therefore, elucidation of the molecular mechanism of E-cadherin endocytosis should be one of the key elements in tumor cell biology.

Figure 1

Assignment of coatmer, adaptor, Arf and ArfGAP to specific pathways of intracellular vesicle trafficking. Each transport route is indicated by an arrow, together with the molecules involved. The molecules are depicted in the following order: coatmer, adaptor, Arf, and ArfGAP. IL‐2R, interleukin‐2 receptor; GPCR, G‐protein coupled receptor; RE, recycling endosome.

Figure 2

Comparison of the subcellular localization of SMAP1 and SMAP2 proteins. HeLa cells were transfected with HA‐tagged SMAP1 (a) or SMAP2 (b), and expressed proteins were detected using immunofluorescence with anti‐HA antibody.

Figure 3

Domain architectures of various ArfGAP proteins. The domain compositions of representative ArfGAPs shown in Figure 1 are depicted. ArfGAP, ArfGAP domain; CB, clathrin box; CALM BD, CALM‐binding domain; A, ankyrin repeat; SHD, spa homology domain; cc, coiled coil domain; SH3, Src homology domain 3; SAM, sterile‐motif domain; GLD, GTP‐binding protein‐like domain. Adapted from Randazzo and Hirsch, with permission from the authors and Elsevier.

Figure 4

Higher‐order complexes possibly formed at the site of vesicle budding from the PM and Golgi membrane. At the PM and Golgi, constituents that form the putative complexes differ, but bear some similarities, as follows: clathrin/AP‐2 (PM) and COPI (Golgi); Arf6 (PM) and Arf1 (Golgi); and SMAP1 (PM) and ArfGAP1 (Golgi).