TNK2 (ACK1)

ACK1 (also known as ACK, TNK2, or activated Cdc42 kinase) is a structurally unique non-receptor tyrosine kinase that is expressed in diverse cell types. This downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. The ACK1 protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. TNK2 integrates signals from plethora of ligand-activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. It binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR. ACK1 transduces extracellular signals to cytosolic and nuclear effectors such as the protein kinase AKT/PKB and androgen receptor (AR), to promote cell survival and growth. TNK2 participates in tumorigenesis, cell survival, and migration. Gene amplification and overexpression of TNK2 were found in many cancer types such as those of the lung and prostate. Recently, four somatic missense mutations of TNK2, which occur in the N-terminal region, the C-lobe of the kinase domain, and the SH3 domain, were identified in cancer tissue samples.

TNK2 (ACK1) Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>ACK1/TNK2

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>ACK1/TNK2

TNK2 (ACK1) Alternative Names

ACK1, TNK2, ACK, FLJ44758, FLJ45547, p21cdc42Hs [Homo sapiens]

ACK1, Tnk2, Ack, AW552477, Cdgip, MGC37479, Pyk1 [Mus musculus]

Summaries for TNK2 (ACK1)

Entrez Gene summary for TNK2:

This TNK2 gene encodes a tyrosine kinase that binds Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. TNK2 may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this TNK2 gene, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

Wikipedia summary for TNK2:

Activated CDC42 kinase 1 is an enzyme that in humans is encoded by the TNK2 gene.

Human TNK2 (ACK1) Protein General Information

 

• Protein names: Tyrosine kinase non-receptor protein 2
• Sequence length: 1038 AA.
• Domain: The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR
  The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation.
  The UBA domain binds both poly- and mono-ubiquitin.
• Sequence similarities: TNK2 belongs to the protein kinase superfamily. Tyr protein kinase family. TNK2 contains 1 CRIB domain. TNK2 contains 1 protein kinase domain. TNK2 contains 1 SH3 domain. TNK2 contains 1 UBA domain.
• Enzyme regulation: TNK2 is inhibited by AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine), which suppresses activating phosphorylation at Tyr-284. Repressed by dasatinib.
• Cofactor: Magnesium.
• Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
  ATP + a protein = ADP + a phosphoprotein.
• Post-translational modification: Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits. Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent
• Subunit structure: TNK2 interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4 By similarity. Homodimer. Interacts with AR, CDC42, WWASL and WWOX. Interacts with CSPG4 (activated). TNK2 interacts with MERTK (activated); stimulates autophosphorylation. TNK2 may interact (phosphorylated) with HSP90AB1; maintains kinase activity. Interacts with NPHP1. Interacts with SNX9 (via SH3 domain). Interacts with SRC (via SH2 and SH3 domain). Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. TNK2 interacts (via kinase domain) with AKT1. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. TNK2 interacts with BCAR1/p130cas via SH3 domains. TNK2 forms complexes with GRB2 and numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by TNK2.
• Subcellular location: Cell membrane. Nucleus. Endosome. Cell junction › adherens junction. Cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side. Cytoplasmic vesicle › clathrin-coated vesicle. Membrane › clathrin-coated pit. Note: The Tyr-284 phosphorylated form is found both in the membrane and nucleus. Co-localizes with EGFR on endosomes. Nuclear translocation is CDC42-dependent.
• Tissue specificity: 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 (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. TNK2 also shows a significant increase in expression in prostate cancers during the progressive stages.
• Sequence caution: The sequence AAH08884.1 differs from that shown. Reason: Unlikely isoform. Aberrant splice sites.

General information above from UniProt

Function for TNK2 (ACK1) Protein

UniProtKB:

TNK2 is non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. TNK2 transduces extracellular signals to cytosolic and nuclear effectors. TNK2 phosphorylates AKT1, AR, MCF2, WASL and WWOX. TNK2 is implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. TNK2 binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. TNK2 may be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. TNK2 phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). TNK2 phosphorylates WWOX on 'Tyr-287'. It phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. TNK2 contributes to the control of AXL receptor levels. TNK2 confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR.

Genatlas:

• TNK2 may be involved in a regulatory mechanism that sustains the GTP-bound active form of CDC42 and which is directly linked to a tyrosine phosphorylation signal transduction pathway
• TNK2 plays a role in transducing CDC42 signals directly to the nucleus
• TNK2 is involved in extracellular matrix-induced integrin signaling, ultimately activating signaling processes like the activation of the small GTPase Rac
• TNK2 is tyrosine kinase linked to many components involved in vesicle dynamics including clathrin, AP2 and synaptojanin-1

Homology for human TNK2 (ACK1)

• homolog to murine Cos1