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activated CDC42 kinase 1; ACK-1; tyrosine kinase non-receptor protein 2 (TNK2, ACK1)
Function:
- non-receptor tyrosine kinase
- regulates activity of a number of proteins by Tyr phosphorylation, especially proteins critical for cell survival, cell growth, & proliferation
- activates AKT1 by phosphorylating it on Tyr-176 resulting in its activation
- phosphorylates AR on Tyr-267 & Tyr-363 & promotes its recruitment to the androgen-responsive enhancers
- phosphorylates WWOX on Tyr-287
- downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1
- binds to both poly- & mono-ubiquitin & regulates ligand- induced degradation of EGFR
- participates in clathrin-mediated endocytosis
- may be involved synaptic function & & plasticity in adult brain as well in brain development
- autophosphorylation regulates kinase activity
- phosphorylation on Tyr-518 is required for interaction with SRC
- ubiquitinated by NEDD4
- its EGF-induced degradation is EGFR activation-dependent & is processed by lysosomes, not proteasomes (putative)
- interacts with CDC42
- interacts with activated CSPG4
- interacts with the androgen receptor
- interacts with WWOX
- interacts with MERTK (activated)
- stimulates autophosphorylation
- may interact (phosphorylated) with HSP90AB1
- maintains kinase activity
- interacts with NPHP1
- interacts with SNX9 (via SH3 domain)
- interacts with SRC (via SH2 domain & SH3 domain)
- interacts with EGFR
- interaction is dependent on EGF stimulation & kinase activity of EGFR
- interacts with NEDD4 (via WW3 domain) & NEDD4L
- EGF promotes its association with NEDD4 (putative)
- interacts (via kinase domain) with AKT1
Cofactor: Mg+2
Inhibition:
- AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine) inhibits its activity & its activation by suppressing phosphorylation at Tyr-284
Structure:
- homodimer
- the EBD (EGFR-binding domain) domain is necessary for interaction with EGFR (putative)
- the SAM-like domain
a) necessary for NEDD4-mediated ubiquitination
b) promotes membrane localization & dimerization to allow for autophosphorylation
- the UBA domain binds both poly- & mono-ubiquitin
- belongs to the protein kinase superfamily, Tyr protein kinase family
- contains 1 CRIB domain
- contains 1 protein kinase domain
- contains 1 SH3 domain
- contains 1 UBA domain
Compartment:
- cell membrane, nucleus, endosome
- cell junction, adherens junction (putative)
- cytoplasmic vesicle membrane
- peripheral membrane protein, cytoplasmic side
- the Tyr-284 phosphorylated form is found both in the membrane & nucleus
- colocalizes with EGFR on the endosomes (putative)
Alternative splicing:
- named isoforms=3
- at least one isoform may show very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay
Pathology:
- the Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ, invasive ductal carcinoma & lymph node metastatic stages
- significant increase in expression in prostate cancers during the progressive stages
Related
CDC42 homolog; cell division control protein 42 homolog; G25K GTP-binding protein (CDC42)
General
tyrosine kinase (protein tyrosine kinase, PTK)
Properties
SIZE: entity length = 1038 aa
MW = 115 kD
COMPARTMENT: cytoplasm
cell nucleus
STATE: active state
MOTIF: SAM-like {1-110}
MOTIF: Thr phosphorylation site {T101}
kinase domain
SITE: 126-385
MOTIF: ATP-binding site
NAME: ATP-binding site
SITE: 132-140
Ser phosphorylation site {S149}
ATP-binding site
NAME: ATP-binding site
SITE: 158-158
aspartate residue {D252}
Tyr phosphorylation site {Y284}
src homology 3 [SH3] domain
SITE: 386-448
CRIB domain {454-466}
Thr phosphorylation site {T517}
Tyr phosphorylation site {Y518}
proline-rich region
SITE: 577-958
MOTIF: proline residue (SEVERAL)
SRC interaction {623-652}
NEDD4 interaction {632-635}
Ser phosphorylation site {S724}
Ser phosphorylation site {S728}
EBD domain {733-876}
Ser phosphorylation site {S785}
Tyr phosphorylation site {Y827}
Tyr phosphorylation site {Y859}
Tyr phosphorylation site {Y860}
Ser phosphorylation site {S881}
Thr phosphorylation site {T925}
UBA domain {958-996}
Database Correlations
OMIM 606994
UniProt Q07912
PFAM correlations
Entrez Gene 10188
Kegg hsa:10188
ENZYME 2.7.10.2
References
- UniProt :accession Q07912
- CGP resequencing studies
http://www.sanger.ac.uk/perl/genetics/CGP/cgp_viewer?action=gene&ln=ACK1