| Accession: | |
|---|---|
| Functional site class: | AAK1 and BIKe phosphorylation site motif |
| Functional site description: | Adaptor-Associated kinase 1 (AAK1) and BMP-2 Inducible Kinase (BIKe) are Serine/Threonine kinases that belong to the Numb-Associated Kinases (NAK). NAKs are reported to play a role in a wide range of cellular functions, including receptor-mediated endocytosis, notch pathway modulation, and dendrite morphogenesis. Specifically, AAK1 and BIKe are known to phosphorylate the endocytic adaptor protein complex 2 protein AP2M1. AAK1 can directly bind clathrin, and it also modulates the Notch cell-to-cell signalling pathway. BIKe has also been found to be associated with clathrin-coated vesicles. Given their endocytic role, AAK1 and BIKe are involved in mediating infection and entry of SARS-CoV-2 and other RNA viruses. The yeast homolog, Prk1p is known to phosphorylate several yeast proteins such as Pan1p, Sla1p and Scd5p, and acts on a similar sequence motif for phosphorylation. |
| ELM Description: | Studies on the Prk1 yeast NAK-family kinase first resulted in the canonical motif for phosphorylation by the NAK family of kinases being reported as L(I).Q.[ST]G (Zeng,1999; Smythe,2003). The human NAK kinase, AAK1 was then shown to phosphorylate the human AP2M1 protein (Q96CW) at a similar site (Ricotta,2002). SPOT arrays confirmed that the two human NAK family kinases AAK1 and BIKe do phosphorylate a similar motif pattern (Johnson,2023). Based on these experiments, the strongest selectivity is found in the T+1 glycine, T-2 glutamine and T-5 isoleucine. For AAK1, positive charge or proline is favourable in position T-1. Depletion of negative charge could be observed at -4 and -5 positions in the AAK1/BIKe phosphosites. Moreover, position -5 disfavours most charged and glycine residues. The positions after T+1 seem to not have any effect on the specificity, except for a slight preference against a negative charge and hydrophobic residues. The motif in ELM enforces the QxTG core of the motif. A more relaxed version of the motif based on the SPOT arrays for exploratory searches is here: [^DEGK]..[QMNDE].(T)G and can be applied in motif search tools. |
| Pattern: | [LIVM][^D][^DEHYWF]Q.(T)G |
| Pattern Probability: | 0.0000309 |
| Present in taxons: | Chordata Fungi |
| Interaction Domain: |
Protein kinase domain (IPR000719)
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases
(Stochiometry: 1 : 1)
|
 Abstract |
The Numb-Associated family of kinases (NAKs) are considered to be functionally diverse and suggested to be potential drug targets in diseases such as myopia, prostate cancer, parkinson’s, osteosarcoma, and amyotrophic lateral sclerosis (AMLS) (Sorrell,2016). The NAK family takes the name from the Drosophila protein NAK, which associates with Numb, playing a part in cell fate determination during cell division. Humans have four paralogous homologs of NAK: AAK1 (adaptor-associated kinase 1), BIKe (BMP-2-inducible kinase, BMP2K), GAK (cyclin G-associated kinase), and MPSK1 (Myristoylated and palmitoylated serine/threonine kinase 1). Two of the paralogs, AAK1 and BIKe, appear to be functionally more equivalent to the founding member of the family and share higher sequence identity to NAK as compared to GAK and MPSK1 (Sorrell,2016). Human NAKs share little sequence conservation except in the kinase domain region (Smythe,2003). In terms of sequence modules, AAK1 and BIKe kinase domains are followed with poly Q and poly Q/H regions, respectively. Whereas, GAK is characterized by a PTEN/Tensin type domain after kinase domain and the MPSK1 sequence primarily contains the kinase domain (Sorrell,2016). AAK1 takes part in receptor-mediated endocytosis by binding to clathrin and phosphorylating the Adaptor protein complex AP-2 mu2 subunit (AP2M1; Q96CW1) at a QxTG motif (Conner,2002). BIKe was reported to play a role in osteoblast differentiation (Kearns,2001). However, the mouse knockout phenotype did not show a bone related phenotype as recorded in the MGI resource (https://www.mousephenotype.org/data/genes/MGI:2155456). BIKe was also observed to associate with clathrin-coated vesicles and has also been shown to phosphorylate the AP2 mu2 subunit, though the site was not identified (Ramesh,2021). AAK1 and BIKe control intracellular trafficking of multiple RNA viruses during viral entry and assembly/egress, including hepatitis C virus (HCV) and dengue virus (DENV) (Neveu,2012; Pu,2020). More recently, a study based on RNAi showed that AAK1 and BIKe are proviral factors in the infection with SARS-CoV-2 (Karim,2022). In fact, several AAK1 inhibitors have been proposed as possible treatments to the acute respiratory disease caused by SARS-CoV-2 (Richardson,2020). The AAK1/GAK inhibitor Baricitinib is used in hospitalised COVID patients as it also inhibits the JAK kinases which have critical roles in macrophages and it would be interesting to know if the AAK1/GAK inhibition also plays a role in the immunomodulatory effects (Meszaros,2021). A canonical NAK-class phosphorylation site motif was observed for the yeast NAK homolog Prk1p, (L(I)xxQxTG) (Zeng,1999). Prk1p has been shown to phosphorylate multiple instances of this motif in Pan1p (P32521; Zeng,1999) in addition to Sla1p (P32790; Zeng,2001) and Scd5p (P34758; Huang,2003). Although, AAK1 and BIKe have a preference for threonine phosphorylation, they accept other hydrophobic residues at position -5, and accept proline and alanine at position -3. The strong preference for a glycine in position +1 is retained, while positions -1 and +2 to +4 show a slight basophilic signal. A noncanonical p-site motif has been reported in the NUMB protein itself but it is semi-buried in a β-sheet and is unlikely to be valid (Sorensen,2008). However, it is noted for completeness. |
6 selected references:
14 GO-Terms:
17 Instances for MOD_AAK1BIKe_LxxQxTG_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Please cite:
The Eukaryotic Linear Motif resource: 2022 release.
(PMID:34718738)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement