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First published online September 7, 2006
doi: 10.1242/10.1242/jcs.03216

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Integrin traffic

VTT Medical Biotechnology, FIN-20520 Turku, Finland

View larger version (12K): [in a new window]   Fig. 1. Integrin cytoplasmic motifs involved in integrin trafficking. The cyto1, cyto2 and cyto3 regions of ß integrins are underlined in the ß1-integrin sequence. The cyto1 sequence is conserved in all ß integrins except ß4, but the cyto2 and cyto3 signals (NxxY) are found in all ß integrins. All three cyto motifs are important for focal adhesion localization. Cyto2 and cyto3 are involved in endocytosis of ß1 integrins (see text). The underlined ß2-integrin tail motif YRRF, the C-terminal ß3-integrin tail and the Arg1161 in 2 integrin are involved in trafficking of Lß2, avß3 and 2ß1, respectively.

View larger version (29K): [in a new window]   Fig. 2. A model for integrin traffic. Integrin-ECM interaction leads to clustering of integrins and formation of focal contacts (FC), where integrins form connections to the actin cytoskeleton through the FAK-Src complex and their substrates (Mitra et al., 2005). Integrin internalization could be coupled to FC disassembly, in which the connection to actin is lost and microtubules are targeted to dynamin-dependent internalization sites (Burridge, 2005; Ezratty et al., 2005). ß1 integrins and ECM proteins are internalized with the help of activated PKC, which binds directly to ß1 integrin cytoplasmic tails (Ng et al., 1999). Internalization of ß1 integrin has been shown to be regulated by Rab5/Rab21 and microtubules (Pellinen et al., 2006), as well as active Arf6. Arf6 is activated by Arf6 GEF (BRAG2), promoting integrin endocytosis (Dunphy et al., 2006), and a similar requirement for GEF activity is likely to exist for Rab5/Rab21-regulated integrin internalization (see text). In the endosomal compartments, ß1 integrins associate with Rab21-GTP in an -subunit cytoplasmic-tail-dependent manner. From these compartments and the perinuclear recycling endosomes (PNRE), the long-loop recycling of ß1 integrins back to the PM has been shown to be regulated by Rab11, Rab21 and Arf6 GTPase activities (Powelka et al., 2004; Roberts et al., 2004). Upon growth-factor stimulation ß3 integrins are diverted to a short-loop recycling pathway involving Rab4 and PKD1 (Woods et al., 2004). The Arf6-dependent recycling of integrins is further regulated by the GTPase-activating protein (GAP) ACAP, which in turn is positively regulated by Akt-mediated phosphorylation. In fibroblasts, the exit of ß1 integrins from recycling endosomes (RE) is also regulated by PKC-mediated phosphorylation of vimentin (Ivaska et al., 2005). Increased transport of 6ß4 integrin to the plasma membrane (PM) has recently been shown to be facilitated by Akt-GSK3ß-dependent stabilization of microtubules (Yoon et al., 2005). The return of integrins to the PM is also dependent on the activity of the PI-3-K-AKT-GSK3 pathway (Roberts et al., 2004).