UniProt functional annotation for Q2M2I8



	UniProt functional annotation for Q2M2I8

UniProt code: Q2M2I8.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis (PubMed:17494869, PubMed:11877457, PubMed:11877461, PubMed:12952931, PubMed:14617351, PubMed:25653444). Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1 (PubMed:17494869). Preferentially, may phosphorylate substrates on threonine residues (PubMed:11877457, PubMed:18657069). Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes (PubMed:12952931). Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes (PubMed:18657069). Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity (PubMed:21464124). {ECO:0000269|PubMed:11877457, ECO:0000269|PubMed:11877461, ECO:0000269|PubMed:12952931, ECO:0000269|PubMed:14617351, ECO:0000269|PubMed:17494869, ECO:0000269|PubMed:18657069, ECO:0000269|PubMed:21464124, ECO:0000269|PubMed:25653444}.

Function: (Microbial infection) By regulating clathrin-mediated endocytosis, AAK1 plays a role in the entry of hepatitis C virus as well as for the lifecycle of other viruses such as Ebola and Dengue. {ECO:0000269|PubMed:25653444, ECO:0000305|PubMed:31136173}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000305};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:11877457, ECO:0000269|PubMed:11877461, ECO:0000269|PubMed:12952931, ECO:0000269|PubMed:14617351, ECO:0000269|PubMed:17494869, ECO:0000269|PubMed:18657069, ECO:0000269|PubMed:26853940, ECO:0000269|PubMed:31136173};

Activity regulation: Stimulated by clathrin. {ECO:0000269|PubMed:14617351, ECO:0000269|PubMed:17494869}.

Subunit: Interacts (via CBD domain) with clathrin (PubMed:17494869, PubMed:14617351). Interacts with AP-2 complex (PubMed:17494869, PubMed:12952931, PubMed:14617351). Interacts with NUMB (PubMed:18657069). Interacts with alpha-adaptin (By similarity). Interacts with EPS15 isoform 2 (PubMed:21464124). Interacts with membrane-bound activated NOTCH1 but not with the inactive full-length form of NOTCH1 (PubMed:21464124). Preferentially interacts with monoubiquitinated activated NOTCH1 compared to the non-ubiquitinated form (PubMed:21464124). {ECO:0000250|UniProtKB:P0C1X8, ECO:0000269|PubMed:12952931, ECO:0000269|PubMed:14617351, ECO:0000269|PubMed:17494869, ECO:0000269|PubMed:18657069, ECO:0000269|PubMed:21464124}.

Subcellular location: Cell membrane {ECO:0000250|UniProtKB:F1MH24}; Peripheral membrane protein {ECO:0000250|UniProtKB:F1MH24}. Membrane, clathrin-coated pit {ECO:0000269|PubMed:11877461}. Cell junction, synapse, presynapse {ECO:0000250|UniProtKB:P0C1X8}. Note=Active when found in clathrin-coated pits at the plasma membrane. In neuronal cells, enriched at presynaptic terminals. In non-neuronal cells, enriched at leading edge of migrating cells. {ECO:0000250|UniProtKB:P0C1X8}.

Tissue specificity: Detected in brain, heart and liver. Isoform 1 is the predominant isoform in brain. {ECO:0000269|PubMed:17494869}.

Ptm: Autophosphorylated. {ECO:0000269|PubMed:17494869}.

Pharmaceutical: By regulating the entry of hepatitis C virus as well as the lifecycle of other viruses such as Ebola and Dengue, AAK1 is a potential drug target for developing antiviral therapies. {ECO:0000305|PubMed:25653444, ECO:0000305|PubMed:31136173}.

Similarity: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Sequence caution: Sequence=BAA83000.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis (PubMed:17494869, PubMed:11877457, PubMed:11877461, PubMed:12952931, PubMed:14617351, PubMed:25653444). Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1 (PubMed:17494869). Preferentially, may phosphorylate substrates on threonine residues (PubMed:11877457, PubMed:18657069). Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes (PubMed:12952931). Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes (PubMed:18657069). Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity (PubMed:21464124). {ECO:0000269\|PubMed:11877457, ECO:0000269\|PubMed:11877461, ECO:0000269\|PubMed:12952931, ECO:0000269\|PubMed:14617351, ECO:0000269\|PubMed:17494869, ECO:0000269\|PubMed:18657069, ECO:0000269\|PubMed:21464124, ECO:0000269\|PubMed:25653444}.



Function:		(Microbial infection) By regulating clathrin-mediated endocytosis, AAK1 plays a role in the entry of hepatitis C virus as well as for the lifecycle of other viruses such as Ebola and Dengue. {ECO:0000269\|PubMed:25653444, ECO:0000305\|PubMed:31136173}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000305};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:11877457, ECO:0000269\|PubMed:11877461, ECO:0000269\|PubMed:12952931, ECO:0000269\|PubMed:14617351, ECO:0000269\|PubMed:17494869, ECO:0000269\|PubMed:18657069, ECO:0000269\|PubMed:26853940, ECO:0000269\|PubMed:31136173};
Activity regulation:		Stimulated by clathrin. {ECO:0000269\|PubMed:14617351, ECO:0000269\|PubMed:17494869}.
Subunit:		Interacts (via CBD domain) with clathrin (PubMed:17494869, PubMed:14617351). Interacts with AP-2 complex (PubMed:17494869, PubMed:12952931, PubMed:14617351). Interacts with NUMB (PubMed:18657069). Interacts with alpha-adaptin (By similarity). Interacts with EPS15 isoform 2 (PubMed:21464124). Interacts with membrane-bound activated NOTCH1 but not with the inactive full-length form of NOTCH1 (PubMed:21464124). Preferentially interacts with monoubiquitinated activated NOTCH1 compared to the non-ubiquitinated form (PubMed:21464124). {ECO:0000250\|UniProtKB:P0C1X8, ECO:0000269\|PubMed:12952931, ECO:0000269\|PubMed:14617351, ECO:0000269\|PubMed:17494869, ECO:0000269\|PubMed:18657069, ECO:0000269\|PubMed:21464124}.
Subcellular location:		Cell membrane {ECO:0000250\|UniProtKB:F1MH24}; Peripheral membrane protein {ECO:0000250\|UniProtKB:F1MH24}. Membrane, clathrin-coated pit {ECO:0000269\|PubMed:11877461}. Cell junction, synapse, presynapse {ECO:0000250\|UniProtKB:P0C1X8}. Note=Active when found in clathrin-coated pits at the plasma membrane. In neuronal cells, enriched at presynaptic terminals. In non-neuronal cells, enriched at leading edge of migrating cells. {ECO:0000250\|UniProtKB:P0C1X8}.
Tissue specificity:		Detected in brain, heart and liver. Isoform 1 is the predominant isoform in brain. {ECO:0000269\|PubMed:17494869}.
Ptm:		Autophosphorylated. {ECO:0000269\|PubMed:17494869}.
Pharmaceutical:		By regulating the entry of hepatitis C virus as well as the lifecycle of other viruses such as Ebola and Dengue, AAK1 is a potential drug target for developing antiviral therapies. {ECO:0000305\|PubMed:25653444, ECO:0000305\|PubMed:31136173}.
Similarity:		Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. {ECO:0000255\|PROSITE-ProRule:PRU00159}.
Sequence caution:		Sequence=BAA83000.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};