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
  • necessary for NEDD4-mediated ubiquitination
  • 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

More general terms

• tyrosine kinase (protein tyrosine kinase, PTK)

Additional terms

• CDC42 homolog; cell division control protein 42 homolog; G25K GTP-binding protein (CDC42)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=10188
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:10188
• OMIM: https://mirror.omim.org/entry/606994
• UniProt: http://www.uniprot.org/uniprot/Q07912.html