Cargo recognition for clathrin-mediated endocytosis (Homo sapiens)

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20, 24, 27, 42, 44...2, 43, 60, 72, 89...2, 16, 40, 50, 54...25, 59, 87, 92454510453, 21, 23, 32, 52...15, 301, 12, 37, 39, 53...14, 56, 60, 71, 1057, 13, 41, 80, 90...83, 95, 98, 99, 1134-6, 18, 26...cytosolDAB2UBC(77-152) COPS7B STAM p-AVPR2 NEDD8-STONs:TOR1hexamer:COP9ADPFCHO1 NECAP1 AVP(20-28) AGFG1PICALMsUBQLN2 PICALM AP2S1 STAM UBC(153-228) VAMP3 LRP2N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT5A(36-380) SNAP91 HGS CLTC ITSN1 SYT8 STON2,1:SYT dimersUBC(609-684) LDLRAP1 PICALM:VAMP2,3,8p-AVPR2 CLTB AP2S1 COPS7A SH3KBP1 AGTR1 CLTC ADBRK1,2REPS2 PI(4,5)P2 PI(4,5)P2 AP-2 cargoEPN2 p-Y850 EPS15 LRP2:DAB2p-6Y-EGFR DAB2 AP-2 ComplexCOPS2 ARRB1 UBC(153-228) EPS15 TOR1B AVP(20-28) AP-2 YXXPhi cargo STON1 COPS8 EPN1 p-Y371-CBL SYT2 AP-2 YXXPhi cargo UBB(77-152) p-Y371-CBL STAM2 EPN1 ARRB1 ARRB2 ARRB:ARRB-bindingGPCRsEPS15 CLTB AP-2 dileucine-containing cargo UBB(153-228) ARRBSH3KBP1 FCHO2 LDLR UBB(1-76) AP2M1 RPS27A(1-76) VAMP2 UBQLN2 Clathrin-mediatedendocytosisEPS15L1 STON1 GPS1 AP2B1 pS-ADRB2 VAMP2 TAGs HGS APOB(28-4563) UBC(77-152) CLTCL1 SH3GL2 AP2M1 EPS15 UBC(533-608) CLTA SH3GL3 PL SYT11 UBC(381-456) TACR1 p-DVL2 SH3GL1 AP2A1 AGTR1 GRB2-1 UBQLN1 RPS27A(1-76) p-DVL2 UBA52(1-76) EPS15L1 CHOL UNQLNs:UIM proteinsEPN2 AP-2:cargoUBC(229-304) p-AVPR2 TOR1A AAK1 AP2M1 ARRB2 SYT9 COPS4 AP2A2(1-939) EGF COPS8 AGTR1 UBB(77-152) GRB2-1 STON2,1NEDD8-STONsREPS1 TOR1 hexamerAP2A2(1-939) COPS3 CLTCL1 SH3GL2 DAB2 CHRM2 UBA52(1-76) DAB2 VAMP7ARRB2 ITSN2 EPS15,EPN1,EPN2EPN1 VAMP8 UBC(305-380) AGFG1 AVP(20-28) AP2A1 CLTC NEDD8(1-88)AP2B1 CHRM2 EPS15 VAMP2,3,8N4GlycoAsn-PalmS WNT5A(36-380) CHRM2 FZD4 FCHO1 LDLRAP1 SGIP1 FZD4 UBC(457-532) AP2A1 LRP2 ADR COPS2 EPN2 UBC(609-684) AP2B1 AP2B1 LDL:LDLR complexSGIP1 SYT11 AP2A1 UBB(153-228) AP2B1 VAMP8 pS-ADRB2 SYT9 SH3GL1 NECAP1 AP2S1 UBQLN1 EPN1 AP2S1 NECAP2 TOR1A AP2A1 COPS5 UBQLN2 EPN2 APOB(28-4563) p-S29-ADRBK1 FZD4 AP2S1 UBC(457-532) UBC(533-608) DAB2,LDLRAP1:LDLR:LDLADR AGFG1:VAMP7AP2A1 SYT dimerspS-ADRB2 UBQLN2,1SH3GL3 ITSN1 UBC(1-76) NAd ARRB1 p-T156 AP2M1 REPS1 VAMP7 AP2A2(1-939) UBC(305-380) STAM2 NEDD8-STON1 EGF PICALM FCHO2 p-AVPR2 UBC(1-76) AVPR2 EPN1 p-Y371-CBL GPS1 ARRB-binding GPCRsTACR1 AP2A2(1-939) TAGs CLTA COPS7B NEDD8-STON1 VAMP3 REPS2 COPS5 UBC(381-456) TACR1 ARBBs:ARBB-bindingGPCRs:clathrin-coated pitSNAP91 AP2M1 CHOL p-T156 AP2M1 COPS4 STON2 AP2S1 p-Y371-CBL SYT1 TOR1B COPS7A CLTA ATPcholesterol esters UBB(1-76) AAK1 EPN1 PL SYT8 COPS6 NEDD8-STON2 COPS6 p-6Y-EGFR AP2B1 NAd UBQLN2:UIM-containing proteinscholesterol esters PI(4,5)P2:p-T156AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1NAd SYT1 NECAP2 ubiquitinated cargoAVPR2:AVP(20-28)EPS15,EPN1,EPN2:ubiquitinated cargoCOPS3 UBC(229-304) ADRBK2 p-DVL2 STON2 CLTA p-Y850 EPS15 AP2A2(1-939) SYT2 p-AVPR2:AVP(20-28)AVP(20-28) LDLR EPS15 AP-2 dileucine-containing cargo ADR ITSN2 AVP(20-28) COP9NEDD8-STON2 EPS15 AP2A2(1-939) DAB2,LDLRAP1CLTC 1318, 49, 51, 61, 70...835, 68, 81, 91, 11618, 49, 51, 61, 70...8, 9, 11, 16, 17, 19...5, 68, 81, 91, 11645


Description

Recruitment of plasma membrane-localized cargo into clathrin-coated endocytic vesicles is mediated by interaction with a variety of clathrin-interacting proteins collectively called CLASPs (clathrin-associated sorting proteins). CLASP proteins, which may be monomeric or tetrameric, are recruited to the plasma membrane through interaction with phosphoinsitides and recognize linear or conformational sequences or post-translational modifications in the cytoplasmic tails of the cargo protein. Through bivalent interactions with clathrin and/or other CLASP proteins, they bridge the recruitment of the cargo to the emerging clathrin coated pit (reviewed in Traub and Bonifacino, 2013). The tetrameric AP-2 complex, first identified in early studies of clathrin-mediated endocytosis, was at one time thought to be the primary CLASP protein involved in cargo recognition at the plasma membrane, and indeed plays a key role in the endocytosis of cargo carrying dileucine- or tyrosine-based motifs.

A number of studies have been performed to test whether AP-2 is essential for all forms of clathrin-mediated endocytosis (Keyel et al, 2006; Motely et al, 2003; Huang et al, 2004; Boucrot et al, 2010; Henne et al, 2010; Johannessen et al, 2006; Gu et al, 2013; reviewed in Traub, 2009; McMahon and Boucrot, 2011). Although depletion of AP-2 differentially affects the endocytosis of different cargo, extensive depletion of AP-2 through RNAi reduces clathrin-coated pit formation by 80-90%, and the CCPs that do form still contain AP-2, highlighting the critcical role of this complex in CME (Johannessen et al, 2006; Boucrot et al, 2010; Henne et al, 2010).


In addition to AP-2, a wide range of other CLASPs including proteins of the beta-arrestin, stonin and epsin families, engage sorting motifs in other cargo and interact either with clathrin, AP-2 or each other to facilitate assembly of a clathin-coated pit (reviewed in Traub and Bonifacino, 2013). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8856825
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Rothfels, Karen

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Bibliography

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  110. Chen W, ten Berge D, Brown J, Ahn S, Hu LA, Miller WE, Caron MG, Barak LS, Nusse R, Lefkowitz RJ.; ''Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4.''; PubMed Europe PMC
  111. Fessart D, Simaan M, Zimmerman B, Comeau J, Hamdan FF, Wiseman PW, Bouvier M, Laporte SA.; ''Src-dependent phosphorylation of beta2-adaptin dissociates the beta-arrestin-AP-2 complex.''; PubMed Europe PMC
  112. Antonescu CN, Aguet F, Danuser G, Schmid SL.; ''Phosphatidylinositol-(4,5)-bisphosphate regulates clathrin-coated pit initiation, stabilization, and size.''; PubMed Europe PMC
  113. Walther K, Diril MK, Jung N, Haucke V.; ''Functional dissection of the interactions of stonin 2 with the adaptor complex AP-2 and synaptotagmin.''; PubMed Europe PMC
  114. Lindwasser OW, Smith WJ, Chaudhuri R, Yang P, Hurley JH, Bonifacino JS.; ''A diacidic motif in human immunodeficiency virus type 1 Nef is a novel determinant of binding to AP-2.''; PubMed Europe PMC
  115. Haglund K, Dikic I.; ''The role of ubiquitylation in receptor endocytosis and endosomal sorting.''; PubMed Europe PMC
  116. Kelly BT, McCoy AJ, Späte K, Miller SE, Evans PR, Höning S, Owen DJ.; ''A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex.''; PubMed Europe PMC
  117. Robinson MS.; ''Forty Years of Clathrin-coated Vesicles.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101633view11:49, 1 November 2018ReactomeTeamreactome version 66
101169view21:36, 31 October 2018ReactomeTeamreactome version 65
100695view20:09, 31 October 2018ReactomeTeamreactome version 64
100245view16:54, 31 October 2018ReactomeTeamreactome version 63
99797view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99347view12:48, 31 October 2018ReactomeTeamreactome version 62
93447view11:23, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AAK1 ProteinQ2M2I8 (Uniprot-TrEMBL)
ADBRK1,2ComplexR-HSA-8866229 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ADR MetaboliteCHEBI:28918 (ChEBI)
ADRBK2 ProteinP35626 (Uniprot-TrEMBL)
AGFG1 ProteinP52594 (Uniprot-TrEMBL)
AGFG1:VAMP7ComplexR-HSA-8863716 (Reactome)
AGFG1ProteinP52594 (Uniprot-TrEMBL)
AGTR1 ProteinP30556 (Uniprot-TrEMBL)
AP-2 ComplexComplexR-HSA-167712 (Reactome)
AP-2 YXXPhi cargo R-HSA-8866232 (Reactome)
AP-2 cargoComplexR-HSA-8866235 (Reactome)
AP-2 dileucine-containing cargo R-HSA-8866234 (Reactome)
AP-2:cargoComplexR-HSA-8866238 (Reactome)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2(1-939) ProteinO94973 (Uniprot-TrEMBL)
AP2B1 ProteinP63010 (Uniprot-TrEMBL)
AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
AP2S1 ProteinP53680 (Uniprot-TrEMBL)
APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
ARBBs:ARBB-binding GPCRs:clathrin-coated pitComplexR-HSA-8866265 (Reactome)
ARRB-binding GPCRsComplexR-HSA-8866250 (Reactome)
ARRB1 ProteinP49407 (Uniprot-TrEMBL)
ARRB2 ProteinP32121 (Uniprot-TrEMBL)
ARRB:ARRB-binding GPCRsComplexR-HSA-8866263 (Reactome)
ARRBComplexR-HSA-1911410 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
AVP(20-28) ProteinP01185 (Uniprot-TrEMBL)
AVPR2 ProteinP30518 (Uniprot-TrEMBL)
AVPR2:AVP(20-28)ComplexR-HSA-392261 (Reactome)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CHRM2 ProteinP08172 (Uniprot-TrEMBL)
CLTA ProteinP09496 (Uniprot-TrEMBL)
CLTB ProteinP09497 (Uniprot-TrEMBL)
CLTC ProteinQ00610 (Uniprot-TrEMBL)
CLTCL1 ProteinP53675 (Uniprot-TrEMBL)
COP9ComplexR-HSA-416968 (Reactome)
COPS2 ProteinP61201 (Uniprot-TrEMBL)
COPS3 ProteinQ9UNS2 (Uniprot-TrEMBL)
COPS4 ProteinQ9BT78 (Uniprot-TrEMBL)
COPS5 ProteinQ92905 (Uniprot-TrEMBL)
COPS6 ProteinQ7L5N1 (Uniprot-TrEMBL)
COPS7A ProteinQ9UBW8 (Uniprot-TrEMBL)
COPS7B ProteinQ9H9Q2 (Uniprot-TrEMBL)
COPS8 ProteinQ99627 (Uniprot-TrEMBL)
Clathrin-mediated endocytosisPathwayR-HSA-8856828 (Reactome) Clathrin-mediated endocytosis (CME) is one of a number of process that control the uptake of material from the plasma membrane, and leads to the formation of clathrin-coated vesicles (Pearse et al, 1975; reviewed in Robinson, 2015; McMahon and Boucrot, 2011; Kirchhausen et al, 2014). CME contributes to signal transduction by regulating the cell surface expression and signaling of receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs). Most RTKs exhibit a robust increase in internalization rate after binding specific ligands; however, some RTKs may also exhibit significant ligand-independent internalization (reviewed in Goh and Sorkin, 2013). CME controls RTK and GPCR signaling by organizing signaling both within the plasma membrane and on endosomes (reviewed in Eichel et al, 2016; Garay et al, 2015; Vieira et al, 1996; Sorkin and von Zastrow, 2014; Di Fiori and von Zastrow, 2014; Barbieri et al, 2016). CME also contributes to the uptake of material such as metabolites, hormones and other proteins from the extracellular space, and regulates membrane composition by recycling membrane components and/or targeting them for degradation.


Clathrin-mediated endocytosis involves initiation of clathrin-coated pit (CCP) formation, cargo selection, coat assembly and stabilization, membrane scission and vesicle uncoating. Although for simplicity in this pathway, the steps leading to a mature CCP are represented in a linear and temporally distinct fashion, the formation of a clathrin-coated vesicle is a highly heterogeneous process and clear temporal boundaries between these processes may not exist (see for instance Taylor et al, 2011; Antonescu et al, 2011; reviewed in Kirchhausen et al, 2014). Cargo selection in particular is a critical aspect of the formation of a mature and stable CCP, and many of the proteins involved in the initiation and maturation of a CCP contribute to cargo selection and are themselves stabilized upon incorporation of cargo into the nascent vesicle (reviewed in Kirchhausen et al, 2014; McMahon and Boucrot, 2011).



Although the clathrin triskelion was identified early as a major component of the coated vesicles, clathrin does not bind directly to membranes or to the endocytosed cargo. Vesicle formation instead relies on many proteins and adaptors that can bind the plasma membrane and interact with cargo molecules. Cargo selection depends on the recognition of endocytic signals in cytoplasmic tails of the cargo proteins by adaptors that interact with components of the vesicle's inner coat. The classic adaptor for clathrin-coated vesicles is the tetrameric AP-2 complex, which along with clathrin was identified early as a major component of the coat. Some cargo indeed bind directly to AP-2, but subsequent work has revealed a large family of proteins collectively known as CLASPs (clathrin- associated sorting proteins) that mediate the recruitment of diverse cargo into the emerging clathrin-coated vesicles (reviewed in Traub and Bonifacino, 2013). Many of these CLASP proteins themselves interact with AP-2 and clathrin, coordinating cargo recruitment with coat formation (Schmid et al, 2006; Edeling et al, 2006; reviewed in Traub and Bonifacino, 2013; Kirchhausen et al, 2014).


Initiation of CCP formation is also influenced by lipid composition, regulated by clathrin-associated phosphatases and kinases (reviewed in Picas et al, 2016). The plasma membrane is enriched in PI(4,5)P2. Many of the proteins involved in initiating clathrin-coated pit formation bind to PI(4,5)P2 and induce membrane curvature through their BAR domains (reviewed in McMahon and Boucrot, 2011; Daumke et al, 2014). Epsin also contributes to early membrane curvature through its Epsin N-terminal homology (ENTH) domain, which promotes membrane curvature by inserting into the lipid bilayer (Ford et al, 2002).

Following initiation, some CCPs progress to formation of vesicles, while others undergo disassembly at the cell surface without producing vesicles (Ehrlich et al, 2004; Loerke et al, 2009; Loerke et al, 2011; Aguet et al, 2013; Taylor et al, 2011). The assembly and stabilization of nascent CCPs is regulated by several proteins and lipids (Mettlen et al, 2009; Antonescu et al, 2011).


Maturation of the emerging clathrin-coated vesicle is accompanied by further changes in the lipid composition of the membrane and increased membrane curvature, promoted by the recruitment of N-BAR domain containing proteins (reviewed in Daumke et al, 2014; Ferguson and De Camilli, 2012; Picas et al, 2016). Some N-BAR domain containing proteins also contribute to the recruitment of the large GTPase dynamin, which is responsible for scission of the mature vesicle from the plasma membrane (Koh et al, 2007; Lundmark and Carlsson, 2003; Soulet et al, 2005; David et al, 1996; Owen et al, 1998; Shupliakov et al, 1997; Taylor et al, 2011; Ferguson et al, 2009; Aguet et al, 2013; Posor et al, 2013; Chappie et al, 2010; Shnyrova et al, 2013; reviewed in Mettlen et al, 2009; Daumke et al, 2014). After vesicle scission, the clathrin coat is dissociated from the new vesicle by the ATPase HSPA8 (also known as HSC70) and its DNAJ cofactor auxilin, priming the vesicle for fusion with a subsequent endocytic compartment and releasing clathrin for reuse (reviewed in McMahon and Boucrot, 2011; Sousa and Laufer, 2015).
DAB2 ProteinP98082 (Uniprot-TrEMBL)
DAB2,LDLRAP1:LDLR:LDLComplexR-HSA-8862887 (Reactome)
DAB2,LDLRAP1ComplexR-HSA-8862885 (Reactome)
DAB2ProteinP98082 (Uniprot-TrEMBL)
EGF ProteinP01133 (Uniprot-TrEMBL)
EPN1 ProteinQ9Y6I3 (Uniprot-TrEMBL)
EPN2 ProteinO95208 (Uniprot-TrEMBL)
EPS15 ProteinP42566 (Uniprot-TrEMBL)
EPS15,EPN1,EPN2:ubiquitinated cargoComplexR-HSA-8866261 (Reactome)
EPS15,EPN1,EPN2ComplexR-HSA-8866243 (Reactome)
EPS15L1 ProteinQ9UBC2 (Uniprot-TrEMBL)
FCHO1 ProteinO14526 (Uniprot-TrEMBL)
FCHO2 ProteinQ0JRZ9 (Uniprot-TrEMBL)
FZD4 ProteinQ9ULV1 (Uniprot-TrEMBL)
GPS1 ProteinQ13098 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
HGS ProteinO14964 (Uniprot-TrEMBL)
ITSN1 ProteinQ15811 (Uniprot-TrEMBL)
ITSN2 ProteinQ9NZM3 (Uniprot-TrEMBL)
LDL:LDLR complexComplexR-HSA-171100 (Reactome)
LDLR ProteinP01130 (Uniprot-TrEMBL)
LDLRAP1 ProteinQ5SW96 (Uniprot-TrEMBL)
LRP2 ProteinP98164 (Uniprot-TrEMBL)
LRP2:DAB2ComplexR-HSA-8862884 (Reactome)
LRP2ProteinP98164 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5A(36-380) ProteinP41221 (Uniprot-TrEMBL)
NAd MetaboliteCHEBI:18357 (ChEBI)
NECAP1 ProteinQ8NC96 (Uniprot-TrEMBL)
NECAP2 ProteinQ9NVZ3 (Uniprot-TrEMBL)
NEDD8(1-88)ProteinQ15843 (Uniprot-TrEMBL)
NEDD8-STON1 ProteinQ9Y6Q2 (Uniprot-TrEMBL)
NEDD8-STON2 ProteinQ8WXE9 (Uniprot-TrEMBL)
NEDD8-STONs:TOR1 hexamer:COP9ComplexR-HSA-8863731 (Reactome)
NEDD8-STONsComplexR-HSA-8863725 (Reactome)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1ComplexR-HSA-8856806 (Reactome)
PICALM ProteinQ13492 (Uniprot-TrEMBL)
PICALM:VAMP2,3,8ComplexR-HSA-8867601 (Reactome)
PICALMsComplexR-HSA-8867602 (Reactome)
PL MetaboliteCHEBI:16247 (ChEBI)
REPS1 ProteinQ96D71 (Uniprot-TrEMBL)
REPS2 ProteinQ8NFH8 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SGIP1 ProteinQ9BQI5 (Uniprot-TrEMBL)
SH3GL1 ProteinQ99961 (Uniprot-TrEMBL)
SH3GL2 ProteinQ99962 (Uniprot-TrEMBL)
SH3GL3 ProteinQ99963 (Uniprot-TrEMBL)
SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
SNAP91 ProteinO60641 (Uniprot-TrEMBL)
STAM ProteinQ92783 (Uniprot-TrEMBL)
STAM2 ProteinO75886 (Uniprot-TrEMBL)
STON1 ProteinQ9Y6Q2 (Uniprot-TrEMBL)
STON2 ProteinQ8WXE9 (Uniprot-TrEMBL)
STON2,1:SYT dimersComplexR-HSA-8862879 (Reactome)
STON2,1ComplexR-HSA-8862880 (Reactome)
SYT dimersComplexR-HSA-8862881 (Reactome)
SYT1 ProteinP21579 (Uniprot-TrEMBL)
SYT11 ProteinQ9BT88 (Uniprot-TrEMBL)
SYT2 ProteinQ8N9I0 (Uniprot-TrEMBL)
SYT8 ProteinQ8NBV8 (Uniprot-TrEMBL)
SYT9 ProteinQ86SS6 (Uniprot-TrEMBL)
TACR1 ProteinP25103 (Uniprot-TrEMBL)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TOR1 hexamerComplexR-HSA-8863573 (Reactome)
TOR1A ProteinO14656 (Uniprot-TrEMBL)
TOR1B ProteinO14657 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBQLN1 ProteinQ9UMX0 (Uniprot-TrEMBL)
UBQLN2 ProteinQ9UHD9 (Uniprot-TrEMBL)
UBQLN2,1ComplexR-HSA-8866241 (Reactome)
UBQLN2:UIM-containing proteinsComplexR-HSA-8866245 (Reactome)
UNQLNs:UIM proteinsComplexR-HSA-8866247 (Reactome)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
VAMP2,3,8ComplexR-HSA-8867604 (Reactome)
VAMP3 ProteinQ15836 (Uniprot-TrEMBL)
VAMP7 ProteinP51809 (Uniprot-TrEMBL)
VAMP7ProteinP51809 (Uniprot-TrEMBL)
VAMP8 ProteinQ9BV40 (Uniprot-TrEMBL)
cholesterol esters MetaboliteCHEBI:17002 (ChEBI)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-AVPR2 ProteinP30518 (Uniprot-TrEMBL)
p-AVPR2:AVP(20-28)ComplexR-HSA-8866248 (Reactome)
p-DVL2 ProteinO14641 (Uniprot-TrEMBL)
p-S29-ADRBK1 ProteinP25098 (Uniprot-TrEMBL)
p-T156 AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
p-Y371-CBL ProteinP22681 (Uniprot-TrEMBL)
p-Y850 EPS15 ProteinP42566 (Uniprot-TrEMBL)
pS-ADRB2 ProteinP07550 (Uniprot-TrEMBL)
ubiquitinated cargoComplexR-HSA-8866252 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADBRK1,2mim-catalysisR-HSA-8866268 (Reactome)
ADPArrowR-HSA-8866268 (Reactome)
AGFG1:VAMP7ArrowR-HSA-8863718 (Reactome)
AGFG1R-HSA-8863718 (Reactome)
AP-2 ComplexR-HSA-8866277 (Reactome)
AP-2 cargoR-HSA-8866277 (Reactome)
AP-2:cargoArrowR-HSA-8866277 (Reactome)
ARBBs:ARBB-binding GPCRs:clathrin-coated pitArrowR-HSA-8866283 (Reactome)
ARRB-binding GPCRsR-HSA-8866269 (Reactome)
ARRB:ARRB-binding GPCRsArrowR-HSA-8866269 (Reactome)
ARRB:ARRB-binding GPCRsR-HSA-8866283 (Reactome)
ARRBR-HSA-8866269 (Reactome)
ATPR-HSA-8866268 (Reactome)
AVPR2:AVP(20-28)R-HSA-8866268 (Reactome)
COP9ArrowR-HSA-8863723 (Reactome)
COP9R-HSA-8863721 (Reactome)
DAB2,LDLRAP1:LDLR:LDLArrowR-HSA-8863471 (Reactome)
DAB2,LDLRAP1R-HSA-8863471 (Reactome)
DAB2R-HSA-8863472 (Reactome)
EPS15,EPN1,EPN2:ubiquitinated cargoArrowR-HSA-8866279 (Reactome)
EPS15,EPN1,EPN2R-HSA-8866275 (Reactome)
EPS15,EPN1,EPN2R-HSA-8866279 (Reactome)
LDL:LDLR complexR-HSA-8863471 (Reactome)
LRP2:DAB2ArrowR-HSA-8863472 (Reactome)
LRP2R-HSA-8863472 (Reactome)
NEDD8(1-88)ArrowR-HSA-8863723 (Reactome)
NEDD8(1-88)R-HSA-8863727 (Reactome)
NEDD8-STONs:TOR1 hexamer:COP9ArrowR-HSA-8863721 (Reactome)
NEDD8-STONs:TOR1 hexamer:COP9R-HSA-8863723 (Reactome)
NEDD8-STONs:TOR1 hexamer:COP9mim-catalysisR-HSA-8863723 (Reactome)
NEDD8-STONsArrowR-HSA-8863727 (Reactome)
NEDD8-STONsR-HSA-8863721 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1R-HSA-8866283 (Reactome)
PICALM:VAMP2,3,8ArrowR-HSA-8867613 (Reactome)
PICALMsR-HSA-8867613 (Reactome)
R-HSA-8863463 (Reactome) Stonin2 (STON2) is a member of a conserved family of adaptor proteins that retrieve plasma-membrane localized synaptic vesicle proteins such as the synaptotagmin (SYT) family after synaptic vesicle release (reviewed in Maritzen et al, 2010). STON2 has a C-terminal mu homology domain that is 30% identical to that of AP-2, and interaction with SYT1 depends on this domain (Jung et al, 2007). STON2 also interacts with the AP2 complex through the STON2 WxxF motifs, and mutation of these residues abrogates SYT1 endocytosis (Walther et al, 2001; Walther et al, 2004; Diril et al, 2006). In addition, STON2 may also interact with other components of the emerging clathrin-coated pit, including EPS15 and ITSN1 (Martina et al, 2001; Rumpf et al, 2008). Although STON2 has been best studied in the context of SYT1 endocytosis, it also interacts with SYT2 and SYT9, and weakly with SYT8 and SYT11 (Diril et al, 2006). Mammalian cells contain another family member, STON1, which may also play a role in synaptic vesicle protein endocytosis, but its role and localization are not as well characterized.
R-HSA-8863471 (Reactome) Internalization of the low density lipoprotein receptor (LDLR) depends on the recognition of its atypical FDNPVY sequence by the CLASP (clathrin-associated sorting protein) LDLRAP1 (also known as ARH) and DAB2, which may be functionally redundant (Chen et al, 1990; Morris et al, 2001; Mishra et al, 2002a; He et al, 2002; Mishra et al, 2002b; Zhou et al, 2003; Mishra et al, 2005). Both DAB2 and LDLRAP1 also interact with both clathrin and AP-2 as well as with PI(4,5)P2 in the plasma membrane (Morris et al, 2001; Mishar et al, 2002a; He et al, 2002; Mishra et al, 2002b; Zhou et al, 2003). Consistent with the notion that cargo contributes to the regulation of CCP formation, overexpression of LDLR results in an increase in abortive CCP turnover, a decrease in the rate of CCP maturation and an increase in CCP size in an LDLRAP1- and DAB2-dependent manner (Mettlen et al, 2010).
R-HSA-8863472 (Reactome) DAB2 interacts by coimmunoprecipitation with the LDL receptor family protein LRP2 (also known as Megalin) through the third intracellular NPxY motif of LRP2 (Gallagher et al, 2004; Oleinikov et al, 2000). While the functional significance of this interaction remains to be elucidated, Dab2-/- mice show phenotypes consistent with reduced LRP2 endocytosis, suggesting that the interaction may help to sort LRP2 into clathrin-coated pits (Morris et al, 2002; Mishra et al, 2002).
R-HSA-8863718 (Reactome) AGFG1, also known as HRB (HIV-1 Rev-binding), is a clathrin adaptor and ArfGAP that interacts with the R-SNARE VAMP7 to mediate its endocytosis from the plasma membrane (Pryor et al, 2008; Chaineau et al, 2008). AGFG1 also interacts with a number of other endocytic proteins such as EPS15, EPS15R, FCHos and ITSNs (Doria et al, 1999; Salcini et al, 1997; Schmid et al, 2006; Umasankar et al, 2012).
R-HSA-8863721 (Reactome) STON2 protein levels are stabilized by deneddylation, restoring the endocytic uptake of SYT1. Deneddylation is mediated by TOR1A and the CSN4 subunit of the COP9 signalosome, both of which directly bind to STON2 (Granata et al, 2011).
R-HSA-8863723 (Reactome) Deneddylation of STON2 by TOR1A and the COP9 signalosome stabilize the protein, allowing it to function in the endocytosis of cargo such as the SYT proteins (Granata et al, 2011).
R-HSA-8863727 (Reactome) STON2 is post-translationally neddylated by an unknown enzyme. Neddylation appears to contribute to STON2 destabilization, possibly by promoting its subsequent ubiquitination and degradation. Decreased STON2 protein levels are associated with increased plasma membrane levels of SYT1, reflecting a defect in its STON2-mediated recapture through endocytosis (Granata et al, 2011).
R-HSA-8866268 (Reactome) AVPR2 is phosphorylated by ADBRK1 and 2 in an agonist-dependent manner as a prerequisite for beta-arrestin binding and endocytosis (Ren et al, 2005; reviewed in Gurevich and Gurevich, 2006).
R-HSA-8866269 (Reactome) Beta arrestins 1 and 2 are required for the endocytosis and downregulation of numerous GPCRs including ADRB2, CHRM2, FZD, C5aR and many others (Ferguson et al, 1995; Goodman et al, 1995; Chen et al, 2003; Gurevich et al, 1995; Braun et al, 2003; reviewed in Kovacs et al, 2009; Traub and Bonifacino, 2013). Beta-arrestin mediated downregulation of GPCRs is modulated by receptor phosphorylation status (see for instance Fessart et al, 2007; Braun et al, 2003; reviewed in Gurevich and Gurevich, 2006). In addition to recognizing GPCR cargo, beta-arrestins also bind directly to the AP-2 complex, thus mediating the recruitment of cargo into nascent clathrin coated vesicles (Edeling et al, 2006; Schmid et al, 2006; reviewed in Traub and Bonifacino, 2013; Kang et al, 2014). A recent study has shown that in addition to mediating GPCR endocytosis, beta-arrestin2 can be recruited to CCPs after dissociation from ADRB2 to promote MAPK signaling, highlighting a role for CCPs as signaling microdomains (Eichel et al, 2016).

R-HSA-8866275 (Reactome) UBQLN proteins, also known as PLIC (protein linking IAP to cytoskeleton), are a family of four proteins with known roles in targeting ubiquitinated proteins to the proteasome (Mah et al, 2000; Kleijnen et al, 2000; Funakoshi et al, 2002). More recently, UBQLN proteins have been shown to play roles in the regulation of GPCR signaling (N'Diaye and Brown, 2003; Regan-Klapisz et al, 2005; N'Diaye et al, 2008). The ubiquitously expressed UBQLN1 and 2 both interact with UIM-domain containing proteins such as EPS15; the interaction is mediated by the UBQLN C-terminal UbL domain (Regan-Klapisz et al, 2005; N'Diaye et al, 2008). In the case of UBQLN2, interaction with UIM-containing proteins is required for UBQLN2 to negatively regulate clathrin-mediated endocytosis of GPCRs (N'Diaye et al, 2008).
R-HSA-8866277 (Reactome) AP-2 is a heterotetrameric complex that was originally identified as a factor required to help assemble clathrin at the plasma membrane to promote endocytosis (Keen et al, 1987; reviewed in Robinson, 2015). In addition to its structural role, AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo such as the transferrin receptor, cation dependent and independent mannose-6-phosphate receptors, CFTR, CD3 and CD4 proteins, glucose transporters and the viral Nef protein, among many others (Collawn et al, 1990; Jadot et al, 1992; Storch and Braulke, 2001; Ohno et al, 1995; Letourneur and Klausner, 1992; Kelly et al, 2008; Schmidt et al, 2006; Doray et al, 2007; Chaudhuri et al, 2007; Lindwasser et al, 2008; Collaco et al, 2010; Fu et al, 2012; reviewed in Traub and Bonifacino, 2013). Both membrane recruitment and interaction of AP-2 with the sorting signals of cargo are mediated by the large 'trunk' domain of AP-2, made up of the medium and small subunits and the N-terminal domains of the 2 large subunits (Collins et al, 2002; Heuser and Keen, 1988; Owen and Evans, 1998; Kelly et al, 2008; reviewed in Traub and Bonifacino, 2013).

AP-2 also facilitates the recruitment of many other endocytic cargo indirectly by binding to CLASP proteins (clathrin associated sorting proteins) that themselves interact with cargo (Schmid et al, 2006; Edeling et al, 2006; reviewed in Traub and Bonifacino, 2013). CLASP proteins generally interact with AP-2 through the globular 'beta-2 ear', one of 2 ear domains made up of the C-terminal regions of the two large subunits (reviewed in Owen, 2004; Schmid and McMahon, 2007).


R-HSA-8866279 (Reactome) Some membrane cargo is sorted into clathrin-coated pits after ubiquitination of the cytosolic domain (reviewed in Piper et al 2014). Ubiquitinated cargo is recognized by adaptor proteins such as EPS15, EPN1 and EPN2 that contain ubiquitin-binding domains and also interact with components of the clathrin coat (Chen et al, 1998; Rosenthal et al, 1999; Polo et al, 2002; Shih et al, 2002; Haglund et al, 2003; Schmid et al, 2006; reviewed in Sen et al, 2012; Piper et al, 2014). A number of receptor tyrosine kinases, including EGFR, VEGFR, FGFR and others undergo ubiquitination at the plasma membrane, triggering endocytosis. Internalized RTKs can undergo recycling or degradation, the latter of which serves to terminate signaling (reviewed in Sorkin and von Zastrow, 2009; Haglund and Dikic, 2012). Ubiquitin-based sorting into CCPs appears to be dynamic as deubiquitinases have been identified as components of some CCPs (Weinberg and Drubin, 2014).
R-HSA-8866283 (Reactome) Interaction between beta-arrestins and components of the clathrin-coat mediate the recruitment of GPCRs into nascent clathrin-coated pits (Shenoy et al, 2001; Goodman et al, 1997; Goodman et al, 1997; Laporte et al, 1999; reviewed in Gurevich and Gurevich, 2006). In the case of the V2 vasopressin receptor (AVPR2) and the beta-2 adrenergic receptor (ADRB2), this beta-arrestin-mediated recruitment into clathrin-coated pits is negatively regulated by UBQLN2, possibly through competition for binding to the UIM-containing proteins such as EPS15, EPN1 and EPN2 (N'Diaye et al, 2008).
R-HSA-8867613 (Reactome) PICALM is a phosphatidylinositol-binding clathrin assembly protein that interacts with PI(4,5)P2 and clathrin and plays a role in recruiting clathrin and AP-2 to nascent coated pits at the plasma membrane (Tebar et al, 1999). In addition, PICALM binds directly to a number of R-SNAREs, including VAMP2,3 and 8 to mediate their inclusion in clathrin-coated pits and subsequent recycling to the endosome where they function (Miller et al, 2011).
STON2,1:SYT dimersArrowR-HSA-8863463 (Reactome)
STON2,1ArrowR-HSA-8863723 (Reactome)
STON2,1R-HSA-8863463 (Reactome)
STON2,1R-HSA-8863727 (Reactome)
SYT dimersR-HSA-8863463 (Reactome)
TOR1 hexamerArrowR-HSA-8863723 (Reactome)
TOR1 hexamerR-HSA-8863721 (Reactome)
UBQLN2,1R-HSA-8866275 (Reactome)
UBQLN2:UIM-containing proteinsTBarR-HSA-8866283 (Reactome)
UNQLNs:UIM proteinsArrowR-HSA-8866275 (Reactome)
VAMP2,3,8R-HSA-8867613 (Reactome)
VAMP7R-HSA-8863718 (Reactome)
p-AVPR2:AVP(20-28)ArrowR-HSA-8866268 (Reactome)
ubiquitinated cargoR-HSA-8866279 (Reactome)
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