Search results for AAK1

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Protein (1 results from a total of 1)

Identifier: R-HSA-8854795
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: AAK1: Q2M2I8

Reaction (4 results from a total of 4)

Identifier: R-HSA-8871193
Species: Homo sapiens
Compartment: clathrin-coated endocytic vesicle membrane
GAPVD1 binds the alpha adaptin ear domain of AP-2 mu2, activating its RAB5-directed GEF activity and displacing AAK1. AAK1 displacement results in a net dephosphorylation of the AP-2 mu2 subunit, destabilizing the interaction of AP-2 with the vesicle membrane (Sato et al, 2005; Smerdjieva et al, 2008). In addition, RAB5 contributes to PI(4,5)P2 turnover through recruitment of a PI3K or PI phosphatase, and this also destabilizes the interaction of AP-2 with the membrane (Smerdjieva et al, 2008; Christoforidis et al, 1999; Shin et al, 2005).
Identifier: R-HSA-8856813
Species: Homo sapiens
Compartment: plasma membrane
AAK1 is a serine-threonine kinase that phosphorylates T156 of the AP2 mu2 subunit (Olusanya et al, 2001; Conner et al, 2002; Conner et al, 2003). This phosphorylation is thought to stabilize the open conformation of the AP-2 complex, exposing the cargo-binding sites and promoting cargo capture (Ricotta et al, 2002). AAK1 kinase activity is stimulated by interaction with clathrin (Conner et al, 2003; Henderson et al, 2007).
Identifier: R-HSA-8856808
Species: Homo sapiens
Compartment: plasma membrane
Recruitment of early acting proteins such as the FCHo and ITSN proteins stabilizes the transient AP-2:clathrin complex at the plasma membrane and is rapidly followed by incorporation of many more molecules of AP-2 and clathrin. AP-2 binding to the plasma-membrane enriched PI(4,5)P2 is reinforced early in the formation of a CCP by the interaction of AP-2 with PIP5K1C, which synthesizes PI(4)P to PI(4,5)P2 (Krauss et al, 2006; Bairstow et al, 2006; Thieman et al, 2009).

AP-2 recruitment is also promoted by conformational changes upon lipid and protein binding. AP-2 is a heterotetramer consisting of two large subunits (alpha and beta1 adaptin), a medium mu2 subunit and a small sigma2 subunit, and exists in a closed conformation when not part of a clathrin-coated pit (Jackson et al, 2010).
Interactions between the AP-2 mu2 subunit and PIP2 within the lipid bilayer stabilize the 'open' conformation of AP-2, exposing binding sites for cargo proteins. The open conformation is also promoted by interaction of AP-2 with early CCP proteins such as SGIP and FCHo2 (Hollopeter et al, 2014). Recruitment of clathrin stimulates the activity of AAK1, an AP-2 kinase that phosphorylates the mu2 subunit of the adaptor complex at Thr156, further stabilizing the open conformation and promoting cargo recruitment (Olusanya et al, 2001; Ricotta et al, 2002; Conner et al, 2002; Conner et al, 2003).

NECAP1 and 2 may also aid in the assembly of an emergent clathrin-coated pit. NECAP proteins have a WxxF motif at the C-terminus that binds with high affinity to the alpha-ear sandwich domain of AP-2 and an N-terminal PH ear domain that interacts both with AP-2 and a wide range of endocytic accessory proteins containing FxDxF motifs (Ritter et al, 2003; Wasiak et al, 2002; Ritter et al, 2013). Clathrin and the NECAP PH ear domain appear to compete for an AP-2 binding site. Clathrin-mediated displacement of the NECAP PH ear domain from its lower affinity AP-2 site may allow release this domain, allowing it to transition to a role in recruiting endocytic accessory proteins and cargo (Ritter et al, 2007; Ritter et al, 2013; reviewed in McMahon and Boucrot, 2011).


Finally, studies have highlighted a role for ARF6 and its GTPase activating protein ARFGAP1 in CCP formation, although the details remain to be established.
ARFGAP1 and ARF6 appear to contribute to the recruitment of some cargo, but may also play a more generalized role in CCP formation (Moravec et al, 2012; Bai et al, 2011). ARFGAP1 binds directly to AP-2 and its GAP activity is required for CME. Consistent with this, silencing of ARFGAP1 impairs CME (Schmid et al, 2006; Rawet et al 2010; Bai et al 2011). ARFGAP1 has activity towards several ARFs, including ARF6 which is found is some CCPs and is known to regulate CME under some circumstances (Moravec et al, 2003; Palacios et al, 2002; Paleotti et al, 2005; Kraus et al, 2003). ARF6 is thought to contribute to the recruitment of AP-2 and clathrin to the plasma membrane, possibly in part by affecting the lipid composition (Paleotti et al, 2002; Krauss et al, 2003).

Identifier: R-HSA-8871194
Species: Homo sapiens
Compartment: clathrin-coated endocytic vesicle membrane
RAB5 is a small GTPase that is implicated in clathrin-mediated endocytosis (Chavrier et al, 1990; McLauchlan et al, 1998; Shin et al, 2002; Taylor et al, 2011; reviewed in Stenmark, 2009; Wandiger-Ness and Zerial, 2014). Recent studies have shown that RAB5 and its associated GEF GAPVD1 may contribute to AP-2 uncoating by displacing AAK1 and promoting the net dephosphorylation of the AP-2 mu2 subunit. This is predicted to destabilize interactions with the plasma membrane and promote uncoating (Sato et al, 2005; Hunker et al, 2006; Smerdjieva et al, 2008). RAB5 and GAPVD1 also increase PI(4,5)P2 turnover, likely through recruitment of a class I PI3K or a PI phosphatase (Christoforidis et al, 1999; Shin et al, 2005).
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