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ACK1 / TNK2  Protein

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Expression host: Baculovirus-Insect Cells  
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ACK1 / TNK2 Related Area

ACK1 / TNK2 Related Pathways

    ACK1 / TNK2 Summary & Protein Information

    ACK1 / TNK2 Background

    Gene Summary: 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]
    General information above from NCBI
    Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:18993068}.; ATP + a protein = ADP + a phosphoprotein. {ECO:0000269|PubMed:18993068}.
    Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
    Enzyme regulation: ENZYME REGULATION: Inhibited by AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine), which suppresses activating phosphorylation at Tyr-284. Repressed by dasatinib. {ECO:0000269|PubMed:20383201, ECO:0000269|PubMed:20623637}.
    Subunit structure: 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). 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 and SH3 domain). Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts (via kinase domain) with AKT1. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with BCAR1/p130cas via SH3 domains. Forms complexes with GRB2 and numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by TNK2. {ECO:0000250, ECO:0000269|PubMed:10587647, ECO:0000269|PubMed:16137687, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16288044, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:17494760, ECO:0000269|PubMed:18477472, ECO:0000269|PubMed:18993068, ECO:0000269|PubMed:19144635, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20979614, ECO:0000269|PubMed:21309750, ECO:0000269|PubMed:8497321}.
    Domain: The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR. {ECO:0000250}.; The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation. {ECO:0000269|PubMed:20979614}.; The UBA domain binds both poly- and mono-ubiquitin. {ECO:0000269|PubMed:20979614}.
    Subcellular location: Cell membrane. Nucleus. Endosome. Cell junction, adherens junction {ECO:0000250}. 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. Colocalizes 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. It also shows a significant increase in expression in prostate cancers during the progressive stages. {ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637}.
    Post-translational: Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits. {ECO:0000269|PubMed:15308621, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637, ECO:0000269|PubMed:20979614, ECO:0000269|PubMed:21169560, ECO:0000269|PubMed:21309750}.; Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent (By similarity). {ECO:0000250}.
    Sequence similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.; Contains 1 CRIB domain. {ECO:0000305}.; Contains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.; Contains 1 SH3 domain. {ECO:0000255|PROSITE-ProRule:PRU00192}.; Contains 1 UBA domain. {ECO:0000305}.
    General information above from UniProt

    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. ACK1 integrates signals from plethora of ligand-activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2 and PDGFR 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. ACK1 participates in tumorigenesis, cell survival, and migration. Gene amplification and overexpression of ACK1 were found in many cancer types such as those of the lung and prostate. Recently, four somatic missense mutations of ACK1, which occur in the N-terminal region, the C-lobe of the kinase domain, and the SH3 domain, were identified in cancer tissue samples.

    ACK1 / TNK2 Alternative Name

    ACK1 / TNK2 Related Studies

  • Mahajan K, et al. (2010) Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. J Cell Physiol. 224(2): 327-33.
  • Chua BT, et al. (2010) Somatic mutation in the ACK1 ubiquitin association domain enhances oncogenic signaling through EGFR regulation in renal cancer derived cells. Mol Oncol. 4(4): 323-34.
  • Prieto-Echage V, et al. (2010) Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1. J Biol Chem. 285(14): 10605-15.